Photochemical crosslinkers for polymer coatings and substrate tie-layer

ABSTRACT

The invention describes novel crosslinking compounds that include photoactivatable moieties. Several families of compounds are disclosed that can include one or more hydrophilic moieties that help to solubilize the compounds in aqueous environments.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of U.S. Ser. No.12/831,673, entitled “Photochemical Crosslinkers for Polymer Coatingsand Substrate Tie-Layer”, filed Jul. 7, 2010, now U.S. Pat. No.8,487,137, which is a continuation application of U.S. Ser. No.11/423,503, entitled “Photochemical Crosslinkers for Polymer Coatingsand Substrate Tie-Layer”, filed Jun. 12, 2006, now U.S. Pat. No.7,772,393 and claims benefit under 35 U.S.C. §119(e) to U.S. Ser. Nos.60/690,018, entitled “Photochemical Crosslinkers for Polymer Coatingsand Substrate Tie-Layer”, filed Jun. 13, 2005, 60/709,330, entitled“Photochemical Crosslinkers for Polymer Coatings and SubstrateTie-Layer”, filed Aug. 18, 2005 and 60/804,222, entitled “PhotochemicalCrosslinkers for Polymer Coatings and Substrate Tie-Layer”, filed Jun.8, 2006, the contents of which are incorporated herein by reference intheir entirety.

FIELD OF THE INVENTION

The invention relates generally to cross linking agents that aregenerally hydrophilic and provide photoactivatable groups. The compoundsare useful as surface coating agents alone or in combination with othertarget molecules such as polymers, biomolecules and the like.

BACKGROUND OF THE INVENTION

There exist many ways to coat, adhere, adsorb, modify, etc. a surfacewith a material, such that the material changes the characteristics ofthe surface. For example, suitable coatings can be prepared that whenapplied to a given surface render the surface hydrophobic. In otherinstances, the coating may provide enhanced ability to bind with atarget molecule, such as a protein.

In particular, there are known crosslinking materials that include alatent reactive group, such as a photoactivatable group. Thecrosslinking material has, in general, at least two photoactivatablegroups, such that one group can be activated and attached to the surfaceof the substrate. The remaining latent group, can then later be, orsimultaneously with the surface attachment, activated to react with atarget molecule such as a polymer or a biomolecule.

There are generally three types of crosslinking materials withphotoactivatable groups. One type is hydrophobic in nature, making itdifficult to dissolve in an aqueous systems. The second type ishydrophilic, but includes quaternary charged moieties. Quaternarycompounds tend to promote non-specific binding of non-target molecules,which is often not a desired result. A third type of crosslinkingmaterial with photoactivatable groups includes negatively “charged”groups, such as carboxylic acids, sulfonic acids, phosphoric acids andthe like. Although these materials are considered to be hydrophilic,they also increase non-specific binding interactions with non-targetedmolecules by the crosslinking material.

Therefore, a need exists for a crosslinking material that includesphotoactivatable groups that is hydrophilic in nature and does notpromote non-specific binding interactions with non-target molecules.

BRIEF SUMMARY OF THE INVENTION

The present invention surprisingly provides unique crosslinking moleculefamilies that include photoactivatable groups. The crosslinkers arehydrophilic in nature and do not promote non-specific bindinginteractions with non-target molecules.

One unique crosslinking molecular family includes compounds having theformula:L-((D-T-C(R¹)(XP)CHR²GR³C(═O)R⁴))_(m).

L is a linking group. D is O, S, SO, SO₂, NR⁵ or CR⁶R⁷. T is(—CH₂—)_(x), (—CH₂CH₂—O—)_(x), (—CH₂CH₂CH₂—O—)_(x),(—CH₂CH₂CH₂CH₂—O—)_(x) or forms a bond. R¹ is a hydrogen atom, an alkyl,alkyloxyalkyl, aryl, aryloxyalkyl or aryloxyaryl group. X is O, S, orNR⁸R⁹. P is a hydrogen atom or a protecting group, with the provisiothat P is absent when X is NR⁸R⁹. R² is a hydrogen atom, an alkyl,alkyloxyalkyl, aryl, aryloxylalkyl or aryloxyaryl group. G is O, S, SO,SO₂, NR¹⁰, (CH₂)_(t)—O— or C═O. R³ and R⁴ are each independently analkyl, aryl, arylalkyl, heteroaryl, or an heteroarylalkyl group, oroptionally, R³ and R⁴ can be tethered together via (—CH₂—)_(q),(—CH₂—)_(r)C═O(—CH₂—)_(s), (—CH₂—)_(r)S(—CH₂—)_(s),(—CH₂—)_(r)S═O(—CH₂—)_(s), (—CH₂—)_(r)S(O)₂(—CH₂—)_(s), or(—CH₂—)_(r)NR(—CH₂—)_(s). R⁵ and R¹⁰ are each independently a hydrogenatom or an alkyl, aryl, or arylalkyl group. R⁶ and R⁷ are eachindependently a hydrogen atom, an alkyl, aryl, arylalkyl, heteroaryl orheteroarylalkyl group. R⁸ and R⁹ are each independently a hydrogen atom,an alkyl, aryl, or arylalkyl group, R is a hydrogen atom, an alkyl groupor an aryl group, q is an integer from 1 to about 7, r is an integerfrom 0 to about 3, s is an integer from 0 to about 3, m is an integerfrom 2 to about 10, t is an integer from 1 to about 10 and x is aninteger from 1 to about 500.

In one aspect, L is a branched or unbranched alkyl chain having betweenabout 2 and about 10 carbon atoms.

In another aspect, D is an oxygen atom (O).

In still another aspect, T is (—CH₂—)_(x) or (—CH₂CH₂—O—)_(x) and x is 1or 2.

In still yet another aspect, R¹ is a hydrogen atom.

In yet another aspect, X is an oxygen atom, O, and P is a hydrogen atom.

In another aspect, R² is a hydrogen atom.

In still another aspect, G is an oxygen atom, O.

In still yet another aspect, R³ and R⁴ are each individually arylgroups, which can be further substituted, and m is 3.

In one particular aspect, L is

D is O, T is (—CH₂—)_(x), R¹ is a hydrogen atom, X is O, P is a hydrogenatom, R² is a hydrogen atom, G is O, R³ and R⁴ are phenyl groups, m is 3and x is 1.

In yet another particular aspect, L is (—CH₂—)_(y), D is O, T is(—CH₂—)_(x), R¹ is a hydrogen atom, X is O, P is a hydrogen atom, R² isa hydrogen atom, G is O, R³ and R⁴ are phenyl groups, m is 2, x is 1 andy is an integer from 2 to about 6, and in particular, y is 2, 4 or 6.

A second unique crosslinking molecular family includes compounds havingthe formula:L-((T-C(R¹)(XP)CHR²GR³C(═O)R⁴))_(m).

L is a linking group. T is (—CH₂—)_(x), (—CH₂CH₂—O—)_(x),(—CH₂CH₂CH₂—O—)_(x), (—CH₂CH₂CH₂CH₂—O—)_(x) or forms a bond. R¹ is ahydrogen atom, an alkyl, alkyloxyalkyl, aryl, aryloxyalkyl oraryloxyaryl group. X is O, S, or NR⁸R⁹. P is a hydrogen atom or aprotecting group, with the provisio that P is absent when X is NR⁸R⁹. R²is a hydrogen atom, an alkyl, alkyloxyalkyl, aryl, aryloxylalkyl oraryloxyaryl group. G is O, S, SO, SO₂, NR¹⁰, (CH₂)_(t)—O— or C═O. R³ andR⁴ are each independently an alkyl, aryl, arylalkyl, heteroaryl, or anheteroarylalkyl group, or optionally, R³ and R⁴ can be tethered togethervia (—CH₂—)_(q), (—CH₂—)_(r)C═O(—CH₂—)_(s), (—CH₂—)_(r)S(—CH₂—)_(s),(—CH₂—)_(r)S═O(—CH₂—)_(s), (—CH₂—)_(r)S(O)₂(—CH₂—)_(s), or(—CH₂—)_(r)NR(—CH₂—)_(s). R¹⁰ is a hydrogen atom or an alkyl, aryl, orarylalkyl group. R⁸ and R⁹ are each independently a hydrogen atom, analkyl, aryl, or arylalkyl group. R is a hydrogen atom, an alkyl group oran aryl group, q is an integer from 1 to about 7, r is an integer from 0to about 3, s is an integer from 0 to about 3, m is an integer from 2 toabout 10, t is an integer from 1 to about 10 and x is an integer from 1to about 500.

In one aspect, L has a formula according to structure (I):

A and J are each independently a hydrogen atom, an alkyl group, an arylgroup, or together with B form a cyclic ring, provided when A and J areeach independently a hydrogen atom, an alkyl group, or an aryl groupthen B is not present, B is NR¹¹, O, or (—CH₂—)_(z), provided when A, Band J form a ring, then A and J are (—CH₂—)_(z) or C═O, R¹¹ is ahydrogen atom, an alkyl group, an aryl group or denotes a bond with T,each z independently is an integer from 0 to 3 and provided when eitherA or J is C═O, then B is NR¹¹, O, or (—CH₂—)_(z) and z must be at least1.

In another aspect T is —CH₂—.

In still another aspect, R¹ is a hydrogen atom.

In still yet another aspect, X is O and P is a hydrogen atom.

In still another aspect, R² is a hydrogen atom.

In yet another aspect, G is O.

In another aspect, R³ and R⁴ are each individually aryl groups.

In still yet another aspect, m is 3, and in particular, A and J are bothC═O and B is N or A and J are both hydrogen atoms.

A third unique crosslinking molecular family includes compounds havingthe formula:L-((TGQR³C(═O)R⁴))_(m).

L is a linking group. T is (—CH₂—)_(x), (—CH₂CH₂—O—)_(x),(—CH₂CH₂CH₂—O—)_(x), (—CH₂CH₂CH₂CH₂—O—)_(x) or forms a bond. G is O, S,SO, SO₂, NR¹⁰, (CH₂)_(t)—O— or C═O. Q is (—CH₂—)_(p), (—CH₂CH₂—O—)_(p),—(CH₂CH₂CH₂—O—)_(p) or (—CH₂CH₂CH₂CH₂—O—)_(p). R³ and R⁴ are eachindependently an alkyl, aryl, arylalkyl, heteroaryl, or anheteroarylalkyl group, or optionally, R³ and R⁴ can be tethered together(—CH₂—)_(q), (—CH₂—)_(r)C═O(—CH₂—)_(s), (—CH₂—)_(r)S(—CH₂—)_(s),(—CH₂—)_(r)S═O(—CH₂—)_(s), (—CH₂—)_(r)S(O)₂(—CH₂—)_(s), or(—CH₂—)_(r)NR(—CH₂—)_(s). R¹⁰ is a hydrogen atom or an alkyl, aryl,alkylaryl or arylalkyl group. R is a hydrogen atom, an alkyl group or anaryl group, q is an integer from 1 to about 7, r is an integer from 0 toabout 3, s is an integer from 0 to about 3, m is an integer from 2 toabout 10, p is an integer from 1 to about 10, t is an integer from 1 toabout 10 and x is an integer from 1 to about 500.

In one aspect, L has a formula according to structure (I):

A and J are each independently a hydrogen atom, an alkyl group, an arylgroup, or together with B form a cyclic ring, provided when A and J areeach independently a hydrogen atom, an alkyl group, or an aryl groupthen B is not present, B is NR¹¹, O, or (—CH₂—)_(z), provided when A, Band J form a ring, then A and J are (—CH₂—)_(z) or C═O, R¹¹ is ahydrogen atom, an alkyl group, an aryl group or denotes a bond with T,each z independently is an integer from 0 to 3 and provided when eitherA or J is C═O, then B is NR¹¹, O, or (—CH₂—)_(z) and z must be at least1.

In one aspect, T is —CH₂—.

In another aspect, G is an oxygen atom, O.

In still another aspect, R³ and R⁴ are each individually aryl groups,which can be substituted, and m is 2.

In still yet another aspect, A and J are both C═O and B is NR¹¹.

In another aspect, A and J are both hydrogen atoms.

In yet another aspect, L has a formula according to structure (II):

R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷ are each independently a hydrogen atom, analkyl or aryl group or denotes a bond with T, provided at least two ofR¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷ are bonded with T and each K, independentlyis CH or N.

A fourth unique crosslinking molecular family includes compounds havingthe formula:L-((GTZR³C(═O)R⁴))_(m)

L is a linking group. T is (—CH₂—)_(x), (—CH₂CH₂—O—)_(x),(—CH₂CH₂CH₂—O—)_(x), (—CH₂CH₂CH₂CH₂—O—)_(x) or forms a bond. G is O, S,SO, SO₂, NR¹⁰, (CH₂)_(t)—O— or C═O. Z can be a C═O, COO or CONH when Tis (—CH₂—)_(x). R³ and R⁴ are each independently an alkyl, aryl,arylalkyl, heteroaryl, or an heteroarylalkyl group, or optionally, R³and R⁴ can be tethered together via (—CH₂—)_(q),(—CH₂—)_(r)C═O(—CH₂—)_(s), (—CH₂—)_(r)S(—CH₂—)_(s),(—CH₂—)_(r)S═O(—CH₂—)_(s), (—CH₂—)_(r)S(O)₂(—CH₂—)_(s), or(—CH₂—)_(r)NR(—CH₂—)_(s). R¹⁰ is a hydrogen atom or an alkyl, aryl,alkylaryl or arylalkyl group. R is a hydrogen atom, an alkyl group or anaryl group, q is an integer from 1 to about 7, r is an integer from 0 toabout 3, s is an integer from 0 to about 3, m is an integer from 2 toabout 10, p is an integer from 1 to about 10, t is an integer from 1 toabout 10 and x is an integer from 1 to about 500.

In one aspect, L has a formula according to structure (I):

A and J are each independently a hydrogen atom, an alkyl group, an arylgroup, or together with B form a cyclic ring, provided when A and J areeach independently a hydrogen atom, an alkyl group, or an aryl groupthen B is not present, B is NR¹¹, O, or (—CH₂—)_(z), provided when A, Band J form a ring, then A and J are (—CH₂—)_(z) or C═O, R¹¹ is ahydrogen atom, an alkyl group, an aryl group or denotes a bond with T,each z independently is an integer from 0 to 3 and provided when eitherA or J is C═O, then B is NR¹¹, O, or (—CH₂—)_(z) and z must be at least1.

In one aspect, T is —CH₂—.

In another aspect, G is an oxygen atom, O.

In still another aspect, R³ and R⁴ are each individually aryl groups,which can be substituted, and m is 2.

In still yet another aspect, A and J are both C═O and B is NR¹¹.

In another aspect, A and J are both hydrogen atoms.

In yet another aspect, L has a formula according to structure (II):

R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷ are each independently a hydrogen atom, analkyl or aryl group or denotes a bond with T, provided at least two ofR¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷ are bonded with T and each K, independentlyis CH or N.

In still yet another aspect, compounds of the present invention providethat R³ and R⁴ are both phenyl groups and are tethered together via aCO, a S or a CH₂.

In yet another aspect, compounds of the present invention provide whenR³ and R⁴ are both phenyl group, the phenyl groups can be substitutedwith at least one CH₃OCH₂CH₂O—.

The compounds of the invention have broad applications. The compoundscan be used in surface modifications. The use of hydrophilic groupsprovide the compounds with water solubility. This physical attributeprovides that the compositions can be used where water soluble agentsare favored.

The inclusion of photoreactive moieties within the compositions providesthat the composition can be used with a wide range of support surfaces.The compositions can be used alone or in combination with othermaterials to provide a desired surface characteristic. The compositions,alone or in combination with another material, provides the treatedsurface having a modified property that can include lubricity,hemocompatability, wettability, hydrophilicity, biocompatibility and/orbacterial adhesion.

In another aspect, the present invention pertains to lubriciouscompositions that include polyvinylpyrrolidone and one or more of thecrosslinkers described herein.

In yet another aspect, the present invention pertains to reactionproducts formed between polyvinylpyrrolidone and the crosslinkersdescribed herein. The reaction product can be a coating that canadvantageously be used to coat catheters and medical devices, providinga surface that is lubricious and remains moist.

In still yet another aspect, the combination of one or more crosslinkersdescribed herein and polyvinylpyrrolidone can be combined to form acoating mixture that can be subjected to photoactivation. This can beperformed on various surfaces, and in particular, on one or moresurfaces of a catheter.

While multiple embodiments are disclosed, still other embodiments of thepresent invention will become apparent to those skilled in the art fromthe following detailed description. As will be apparent, the inventionis capable of modifications in various obvious aspects, all withoutdeparting from the spirit and scope of the present invention.Accordingly, the detailed descriptions are to be regarded asillustrative in nature and not restrictive.

DETAILED DESCRIPTION

The present invention surprisingly provides unique crosslinking moleculefamilies that include photoactivatable groups. The crosslinkers arehydrophilic in nature and do not promote non-specific bindinginteractions with non-target molecules.

The compounds of the invention are useful as coating agents. Thecompounds are derived from three different types of molecular families.Each family includes one or more hydrophilic portions, i.e., a hydroxylgroup (that may be protected), amines, alkoxy groups, etc. In oneembodiment the family has the formula:L-((D-T-C(R¹)(XP)CHR²GR³C(═O)R⁴))_(m).

L is a linking group. D is O, S, SO, SO₂, NR⁵ or CR⁶R⁷. T is(—CH₂—)_(x), (—CH₂CH₂—O—)_(x), (—CH₂CH₂CH₂—O—)_(x),(—CH₂CH₂CH₂CH₂—O—)_(x) or forms a bond. R¹ is a hydrogen atom, an alkyl,alkyloxyalkyl, aryl, aryloxyalkyl or aryloxyaryl group. X is O, S, orNR⁸R⁹. P is a hydrogen atom or a protecting group, with the provisiothat P is absent when X is NR⁸R⁹. R² is a hydrogen atom, an alkyl,alkyloxyalkyl, aryl, aryloxylalkyl or aryloxyaryl group. G is O, S, SO,SO₂, NR¹⁰, (CH₂)_(t)—O— or C═O. R³ and R⁴ are each independently analkyl, aryl, arylalkyl, heteroaryl, or a heteroarylalkyl group, oroptionally, R³ and R⁴ can be tethered together via (—CH₂—)_(q),(—CH₂—)_(r)C═O(—CH₂—)_(s), (—CH₂—)_(r)S(—CH₂—)_(s),(—CH₂—)_(r)S═O(—CH₂—)_(s), (—CH₂—)_(r)S(O)₂(—CH₂—)_(s), or(—CH₂—)_(r)NR(—CH₂—)_(s). R⁵ and R⁶ are each independently a hydrogenatom or an alkyl, aryl, or arylalkyl group. R⁶ and R⁷ are eachindependently a hydrogen atom, an alkyl, aryl, arylalkyl, heteroaryl orheteroarylalkyl group. R⁸ and R⁹ are each independently a hydrogen atom,an alkyl, aryl, or arylalkyl group, R is a hydrogen atom, an alkyl groupor an aryl group, q is an integer from 1 to about 7, r is an integerfrom 0 to about 3, s is an integer from 0 to about 3, m is an integerfrom 2 to about 10, t is an integer from 1 to about 10 and x is aninteger from 1 to about 500.

In one aspect, L is a branched or unbranched alkyl chain having betweenabout 2 and about 10 carbon atoms.

In another aspect, D is an oxygen atom (O).

In still another aspect, T is (—CH₂—)_(x) or (—CH₂CH₂—O—)_(x) and x is 1or 2.

In still yet another aspect, R¹ is a hydrogen atom.

In yet another aspect, X is an oxygen atom, O, and P is a hydrogen atom.

In another aspect, R² is a hydrogen atom.

In still another aspect, G is an oxygen atom, O.

In still yet another aspect, R³ and R⁴ are each individually arylgroups, which can be further substituted, and m is 3.

In one particular aspect, L is

D is O, T is (—CH₂—)_(x), R¹ is a hydrogen atom, X is O, P is a hydrogenatom, R² is a hydrogen atom, G is O, R³ and R⁴ are phenyl groups, m is 3and x is 1.

In yet another particular aspect, L is (—CH₂—)_(y), D is O, T is(—CH₂—)_(x), R¹ is a hydrogen atom, X is O, P is a hydrogen atom, R² isa hydrogen atom, G is O, R³ and R⁴ are phenyl groups, m is 2, x is 1 andy is an integer from 2 to about 6, and in particular, y is 2, 4 or 6.

In certain embodiments, x is an integer from about 1 to about 500, moreparticularly from about 1 to about 400, from about 1 to about 250, fromabout 1 to about 200, from about 1 to about 150, from about 1 to about100, from about 1 to about 50, from about 1 to about 25 or from about 1to about 10

In another embodiment, the family has the formula:L-((T-C(R¹)(XP)CHR²GR³C(═O)R⁴))_(m).

wherein L, T, R¹, X, P, R², G, R³, R⁴, R⁸, R⁹, R¹⁰, R, q, r, s, m, t andx are as defined above.

In one aspect, L has a formula according to structure (I):

A and J are each independently a hydrogen atom, an alkyl group, an arylgroup, or together with B form a cyclic ring, provided when A and J areeach independently a hydrogen atom, an alkyl group, or an aryl groupthen B is not present, B is NR¹¹, O, or (—CH₂—)_(z), provided when A, Band J form a ring, then A and J are (—CH₂—)_(z) or C═O, R¹¹ is ahydrogen atom, an alkyl group, an aryl group or denotes a bond with T,each z independently is an integer from 0 to 3 and provided when eitherA or J is C═O, then B is NR¹¹, O, or (—CH₂—)_(z) and z must be at least1.

In another aspect T is —CH₂—.

In another embodiment, the family has the formula:L-((GTZR³C(═O)R⁴))_(m)

wherein L, T, G, R³, R⁴, R¹⁰, R, q, r, s, m, t and x are as definedabove. Z can be a C═O, COO or CONH when T is (—CH₂—)_(x).

In one aspect, L has a formula according to structure (I):

wherein A, B, J, R¹¹, and z are as defined above.

In another aspect, L has a formula according to structure (II):

R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷ are each independently a hydrogen atom, analkyl or aryl group or denotes a bond with T, provided at least two ofR¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷ are bonded with T and each K, independentlyis CH or N.

In another embodiment, the family has the formula:L-((TGQR³C(═O)R⁴))_(m)

wherein L, G, R³, R⁴, R¹⁰, R, q, r, s, m, t and x are as defined above.T is (—CH₂—)_(x), (—CH₂CH₂—O—)_(x), (—CH₂CH₂CH₂—O—)_(x),(—CH₂CH₂CH₂CH₂—O—)_(x) or forms a bond. Q is (—CH₂—)_(p),(—CH₂CH₂—O—)_(p), (—CH₂CH₂CH₂—O—)_(p) or (—CH₂CH₂CH₂CH₂—O—)_(p) and p isan integer from 1 to about 10.

In one aspect, L has a formula according to structure (I):

wherein A, B, J, R¹¹, and z are as defined above.

In another aspect, L has a formula according to structure (II):

R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷ are each independently a hydrogen atom, analkyl or aryl group or denotes a bond with T, provided at least two ofR¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷ are bonded with T and each K, independentlyis CH or N.

In still yet another aspect, compounds of the present invention providethat R³ and R⁴ are both phenyl groups and are tethered together via aCO, a S or a CH₂.

In yet another aspect, compounds of the present invention provide whenR³ and R⁴ are phenyl groups, the phenyl groups can each independently besubstituted with at least one alkyloxyalkyl group, such asCH₃O—(CH₂CH₂O—)_(n)—, or CH₃O(—CH₂CH₂CH₂O—)_(n)-a hydroxylated alkoxygroup, such as HO—CH₂CH₂O—, HO(—CH₂CH₂O—)_(n)— or HO(—CH₂CH₂CH₂O—)_(n)—,etc. wherein n is an integer from 1 to about 10.

In another embodiment the family has the formula:L-((—CH₂—)_(xx)C(R¹)(GR³C(═O)R⁴)₂)_(m)

wherein L, each R, R¹, each G, each R³, each R⁴, each R¹⁰, each q, eachr, each s, each t and m are as defined above and xx is an integer from 1to about 10.

In one aspect, L has a formula according to structure (I):

wherein A, B, J, R¹¹, and z are as defined above.

In another aspect, A and B are both hydrogen atoms.

In still another aspect, xx is 1.

In yet another aspect, R¹ is H.

In still yet another aspect, G is (—CH₂—)_(t)O— and t is 1.

In another aspect, R³ and R⁴ are each individually aryl groups.

In still yet another embodiment, xx is 1, R¹ is H, each G is(—CH₂—)_(t)O—, t is 1 and each of R³ and R⁴ are each individually arylgroups.

In another embodiment of the invention, the family has the formulaL-((—C(R¹)(XP)CHR²GR³C(═O)R⁴)_(m)

where L, R, R¹, R², R³, R⁴, R⁸, R⁹, R¹⁰, X, A P, G, q, r, s, t, and mare as defined above.

In one aspect, L is

and R²⁰ and R²¹ are each individually a hydrogen atom, an alkyl group oran aryl group.

In another aspect, R¹ is H.

In still another aspect, wherein X is O.

In yet another aspect, P is H.

In still yet another aspect, R² is H.

In another aspect, G is (—CH₂—)_(t)O— and t is 1.

In still another aspect, R³ and R⁴ are each individually aryl groups.

In yet another aspect, R¹ is H, X is O, P is H, R² is H, G is(—CH₂—)_(t)O—, t is 1, R³ and R⁴ are each individually aryl groups andR²⁰ and R²¹ are both methyl groups.

In yet another embodiment, the present invention provides a family ofcompounds having the formula:L-((GR³C(═O)R⁴))_(m);

where L, G, R, R³, R⁴, R¹⁰, q, r, s, m and t are as defined above.

In one aspect, L is

In another aspect, G is C═O.

In still another aspect, R³ and R⁴ are each individually aryl groups.

In yet another aspect, G is C═O and R³ and R⁴ are each individually arylgroups.

“Alkyl” by itself or as part of another substituent refers to asaturated or unsaturated branched, straight-chain or cyclic monovalenthydrocarbon radical having the stated number of carbon atoms (i.e.,C1-C6 means one to six carbon atoms) that is derived by the removal ofone hydrogen atom from a single carbon atom of a parent alkane, alkeneor alkyne. Typical alkyl groups include, but are not limited to, methyl;ethyls such as ethanyl, ethenyl, ethynyl; propyls such as propan-1-yl,propan-2-yl, cyclopropan-1-yl, prop-1-en-1-yl, prop-1-en-2-yl,prop-2-en-1-yl, cycloprop-1-en-1-yl; cycloprop-2-en-1-yl,prop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butyls such as butan-1-yl,butan-2-yl, 2-methyl-propan-1-yl, 2-methyl-propan-2-yl, cyclobutan-1-yl,but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl,but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl,cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl,but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, etc.; and the like. Wherespecific levels of saturation are intended, the nomenclature “alkanyl,”“alkenyl” and/or “alkynyl” is used, as defined below. “Lower alkyl”refers to alkyl groups having from 1 to 6 carbon atoms.

“Alkanyl” by itself or as part of another substituent refers to asaturated branched, straight-chain or cyclic alkyl derived by theremoval of one hydrogen atom from a single carbon atom of a parentalkane. Typical alkanyl groups include, but are not limited to,methanyl; ethanyl; propanyls such as propan-1-yl, propan-2-yl(isopropyl), cyclopropan-1-yl, etc.; butanyls such as butan-1-yl,butan-2-yl (sec-butyl), 2-methyl-propan-1-yl (isobutyl),2-methyl-propan-2-yl (t-butyl), cyclobutan-1-yl, etc.; and the like.

“Alkenyl” by itself or as part of another substituent refers to anunsaturated branched, straight-chain or cyclic alkyl having at least onecarbon-carbon double bond derived by the removal of one hydrogen atomfrom a single carbon atom of a parent alkene. The group may be in eitherthe cis or trans conformation about the double bond(s). Typical alkenylgroups include, but are not limited to, ethenyl; propenyls such asprop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl, prop-2-en-2-yl,cycloprop-1-en-1-yl; cycloprop-2-en-1-yl; butenyls such asbut-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl,but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl,cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl, etc.;and the like.

“Alkyloxyalkyl” refers to a moiety having two alkyl groups tetheredtogether via an oxygen bond. Suitable alkyloxyalkyl groups includepolyoxyalkylenes, such as polyethyleneoxides, polypropyleneoxides, etc.that are terminated with an alkyl group, such as a methyl group. Ageneral formula for such compounds can be depicted as R′—(OR″)_(n) or(R′O)_(n)—R″ wherein n is an integer from 1 to about 10, and R′ and R″are alkyl or alkylene groups.

“Alkynyl” by itself or as part of another substituent refers to anunsaturated branched, straight-chain or cyclic alkyl having at least onecarbon-carbon triple bond derived by the removal of one hydrogen atomfrom a single carbon atom of a parent alkyne. Typical alkynyl groupsinclude, but are not limited to, ethynyl; propynyls such asprop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butynyls such as but-1-yn-1-yl,but-1-yn-3-yl, but-3-yn-1-yl, etc.; and the like.

“Alkyldiyl” by itself or as part of another substituent refers to asaturated or unsaturated, branched, straight-chain or cyclic divalenthydrocarbon group having the stated number of carbon atoms (i.e., C1-C6means from one to six carbon atoms) derived by the removal of onehydrogen atom from each of two different carbon atoms of a parentalkane, alkene or alkyne, or by the removal of two hydrogen atoms from asingle carbon atom of a parent alkane, alkene or alkyne. The twomonovalent radical centers or each valency of the divalent radicalcenter can form bonds with the same or different atoms. Typicalalkyldiyl groups include, but are not limited to, methandiyl; ethyldiylssuch as ethan-1,1-diyl, ethan-1,2-diyl, ethen-1,1-diyl, ethen-1,2-diyl;propyldiyls such as propan-1,1-diyl, propan-1,2-diyl, propan-2,2-diyl,propan-1,3-diyl, cyclopropan-1,1-diyl, cyclopropan-1,2-diyl,prop-1-en-1,1-diyl, prop-1-en-1,2-diyl, prop-2-en-1,2-diyl,prop-1-en-1,3-diyl, cycloprop-1-en-1,2-diyl, cycloprop-2-en-1,2-diyl,cycloprop-2-en-1,1-diyl, prop-1-yn-1,3-diyl, etc.; butyldiyls such as,butan-1,1-diyl, butan-1,2-diyl, butan-1,3-diyl, butan-1,4-diyl,butan-2,2-diyl, 2-methyl-propan-1,1-diyl, 2-methyl-propan-1,2-diyl,cyclobutan-1,1-diyl; cyclobutan-1,2-diyl, cyclobutan-1,3-diyl,but-1-en-1,1-diyl, but-1-en-1,2-diyl, but-1-en-1,3-diyl,but-1-en-1,4-diyl, 2-methyl-prop-1-en-1,1-diyl,2-methanylidene-propan-1,1-diyl, buta-1,3-dien-1,1-diyl,buta-1,3-dien-1,2-diyl, buta-1,3-dien-1,3-diyl, buta-1,3-dien-1,4-diyl,cyclobut-1-en-1,2-diyl, cyclobut-1-en-1,3-diyl, cyclobut-2-en-1,2-diyl,cyclobuta-1,3-dien-1,2-diyl, cyclobuta-1,3-dien-1,3-diyl,but-1-yn-1,3-diyl, but-1-yn-1,4-diyl, buta-1,3-diyn-1,4-diyl, etc.; andthe like. Where specific levels of saturation are intended, thenomenclature alkanyldiyl, alkenyldiyl and/or alkynyldiyl is used. Whereit is specifically intended that the two valencies be on the same carbonatom, the nomenclature “alkylidene” is used. A “lower alkyldiyl” is analkyldiyl group having from 1 to 6 carbon atoms. In preferredembodiments the alkyldiyl groups are saturated acyclic alkanyldiylgroups in which the radical centers are at the terminal carbons, e.g.,methandiyl (methano); ethan-1,2-diyl (ethano); propan-1,3-diyl(propano); butan-1,4-diyl (butano); and the like (also referred to asalkylenes, defined infra).

“Alkylene” by itself or as part of another substituent refers to astraight-chain saturated or unsaturated alkyldiyl group having twoterminal monovalent radical centers derived by the removal of onehydrogen atom from each of the two terminal carbon atoms ofstraight-chain parent alkane, alkene or alkyne. The locant of a doublebond or triple bond, if present, in a particular alkylene is indicatedin square brackets. Typical alkylene groups include, but are not limitedto, methylene (methano); ethylenes such as ethano, etheno, ethyno;propylenes such as propano, prop[1]eno, propa[1,2]dieno, prop[1]yno,etc.; butylenes such as butano, but[1]eno, but[2]eno, buta[1,3]dieno,but[1]yno, but[2]yno, buta[1,3]diyno, etc.; and the like. Where specificlevels of saturation are intended, the nomenclature alkano, alkenoand/or alkyno is used. In preferred embodiments, the alkylene group is(C1-C6) or (C1-C3) alkylene. Also preferred are straight-chain saturatedalkano groups, e.g., methano, ethano, propano, butano, and the like.

“Aryl” by itself or as part of another substituent refers to amonovalent aromatic hydrocarbon group having the stated number of carbonatoms (i.e., C5-C15 means from 5 to 15 carbon atoms) derived by theremoval of one hydrogen atom from a single carbon atom of a parentaromatic ring system. Typical aryl groups include, but are not limitedto, groups derived from aceanthrylene, acenaphthylene,acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene,fluoranthene, fluorene, hexacene, hexaphene, hexylene, as-indacene,s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene,ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene,phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene,rubicene, triphenylene, trinaphthalene, and the like, as well as thevarious hydro isomers thereof. In preferred embodiments, the aryl groupis (C5-C15) aryl, with (C5-C10) being even more preferred. Particularlypreferred aryls are phenyl and naphthyl.

“Arylalkyl” by itself or as part of another substituent refers to anacyclic alkyl radical in which one of the hydrogen atoms bonded to acarbon atom, typically a terminal or sp³ carbon atom, is replaced withan aryl group. Typical arylalkyl groups include, but are not limited to,benzyl, 2-phenylethan-1-yl, 2-phenylethen-1-yl, naphthylmethyl,2-naphthylethan-1-yl, 2-naphthylethen-1-yl, naphthobenzyl,2-naphthophenylethan-1-yl and the like. Where specific alkyl moietiesare intended, the nomenclature arylalkanyl, arylalkenyl and/orarylalkynyl is used. Preferably, an arylalkyl group is (C₇-C₃₀)arylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of the arylalkylgroup is (C₁-C₁₀) and the aryl moiety is (C₆-C₂₀), more preferably, anarylalkyl group is (C₇-C₂₀) arylalkyl, e.g., the alkanyl, alkenyl oralkynyl moiety of the arylalkyl group is (C₁-C₈) and the aryl moiety is(C₆-C₁₂).

“Aryloxyalkyl” refers to a moiety having an aryl group and an alkylgroup tethered together via an oxygen bond. Suitable aryloxyalkyl groupsinclude phenyloxyalkylenes, such as methoxyphenyl, ethoxyphenyl, etc.

“Cycloalkyl” by itself or as part of another substituent refers to acyclic version of an “alkyl” group. Typical cycloalkyl groups include,but are not limited to, cyclopropyl; cyclobutyls such as cyclobutanyland cyclobutenyl; cyclopentyls such as cyclopentanyl and cycloalkenyl;cyclohexyls such as cyclohexanyl and cyclohexenyl; and the like.

“Cycloheteroalkyl” by itself or as part of another substituent refers toa saturated or unsaturated cyclic alkyl radical in which one or morecarbon atoms (and any associated hydrogen atoms) are independentlyreplaced with the same or different heteroatom. Typical heteroatoms toreplace the carbon atom(s) include, but are not limited to, N, P, O, S,Si, etc. Where a specific level of saturation is intended, thenomenclature “cycloheteroalkanyl” or “cycloheteroalkenyl” is used.Typical cycloheteroalkyl groups include, but are not limited to, groupsderived from epoxides, imidazolidine, morpholine, piperazine,piperidine, pyrazolidine, pyrrolidine, quinuclidine, and the like.

“Halogen” or “Halo” by themselves or as part of another substituent,unless otherwise stated, refer to fluoro, chloro, bromo and iodo.

“Haloalkyl” by itself or as part of another substituent refers to analkyl group in which one or more of the hydrogen atoms are replaced witha halogen. Thus, the term “haloalkyl” is meant to includemonohaloalkyls, dihaloalkyls, trihaloalkyls, etc. up to perhaloalkyls.For example, the expression “(C1-C2) haloalkyl” includes fluoromethyl,difluoromethyl, trifluoromethyl, 1-fluoroethyl, 1,1-difluoroethyl,1,2-difluoroethyl, 1,1,1-trifluoroethyl, perfluoroethyl, etc.

“Heteroalkyl, Heteroalkanyl, Heteroalkenyl, Heteroalkynyl” by itself oras part of another substituent refer to alkyl, alkanyl, alkenyl andalkynyl radical, respectively, in which one or more of the carbon atoms(and any associated hydrogen atoms) are each independently replaced withthe same or different heteroatomic groups. Typical heteroatomic groupsinclude, but are not limited to, —O—, —S—, —O—O—, —S—S—, —O—S—, —NR′—,═N—N═, —N═N—, —N═N—NR′—, —PH—, —P(O)₂—, —O—P(O)₂—, —S(O)—, —S(O)₂—,—SnH₂— and the like, where R′ is hydrogen, alkyl, substituted alkyl,cycloalkyl, substituted cycloalkyl, aryl or substituted aryl.

“Heteroaryl” by itself or as part of another substituent, refers to amonovalent heteroaromatic radical derived by the removal of one hydrogenatom from a single atom of a parent heteroaromatic ring system. Typicalheteroaryl groups include, but are not limited to, groups derived fromacridine, arsindole, carbazole, β-carboline, benzoxazine, benzimidazole,chromane, chromene, cinnoline, furan, imidazole, indazole, indole,indoline, indolizine, isobenzofuran, isochromene, isoindole,isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine,oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline,phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole,pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline,quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole,thiophene, triazole, xanthene, and the like. Preferably, the heteroarylgroup is from 5-20 membered heteroaryl, more preferably from 5-10membered heteroaryl. Preferred heteroaryl groups are those derived fromthiophene, pyrrole, benzothiophene, benzofuran, indole, pyridine,quinoline, imidazole, oxazole and pyrazine.

“Heteroarylalkyl” by itself or as part of another substituent refers toan acyclic alkyl group in which one of the hydrogen atoms bonded to acarbon atom, typically a terminal or sp³ carbon atom, is replaced with aheteroaryl group. Where specific alkyl moieties are intended, thenomenclature heteroarylalkanyl, heteroarylakenyl and/orheteroarylalkynyl is used. In preferred embodiments, the heteroarylalkylgroup is a 6-21 membered heteroarylalkyl, e.g., the alkanyl, alkenyl oralkynyl moiety of the heteroarylalkyl is (C1-C6) alkyl and theheteroaryl moiety is a 5-15-membered heteroaryl. In particularlypreferred embodiments, the heteroarylalkyl is a 6-13 memberedheteroarylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety is (C1-C3)alkyl and the heteroaryl moiety is a 5-10 membered heteroaryl.

“Hydroxyalkyl” by itself or as part of another substituent refers to analkyl group in which one or more of the hydrogen atoms are replaced witha hydroxyl substituent. Thus, the term “hydroxyalkyl” is meant toinclude monohydroxyalkyls, dihydroxyalkyls, trihydroxyalkyls, etc.

“Parent Aromatic Ring System” refers to an unsaturated cyclic orpolycyclic ring system having a conjugated π electron system.Specifically included within the definition of “parent aromatic ringsystem” are fused ring systems in which one or more of the rings arearomatic and one or more of the rings are saturated or unsaturated, suchas, for example, fluorene, indane, indene, phenalene,tetrahydronaphthalene, etc. Typical parent aromatic ring systemsinclude, but are not limited to, aceanthrylene, acenaphthylene,acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene,fluoranthene, fluorene, hexacene, hexaphene, hexylene, indacene,s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene,ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene,phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene,rubicene, tetrahydronaphthalene, triphenylene, trinaphthalene, and thelike, as well as the various hydro isomers thereof.

“Parent Heteroaromatic Ring System” refers to a parent aromatic ringsystem in which one or more carbon atoms (and any associated hydrogenatoms) are independently replaced with the same or different heteroatom.Typical heteroatoms to replace the carbon atoms include, but are notlimited to, N, P, O, S, Si, etc. Specifically included within thedefinition of “parent heteroaromatic ring systems” are fused ringsystems in which one or more of the rings are aromatic and one or moreof the rings are saturated or unsaturated, such as, for example,arsindole, benzodioxan, benzofuran, chromane, chromene, indole,indoline, xanthene, etc. Typical parent heteroaromatic ring systemsinclude, but are not limited to, arsindole, carbazole, β-carboline,chromane, chromene, cinnoline, furan, imidazole, indazole, indole,indoline, indolizine, isobenzofuran, isochromene, isoindole,isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine,oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline,phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole,pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline,quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole,thiophene, triazole, xanthene, and the like.

“Leaving group” is a group that is displaced during a reaction by anucleophilic reagent. Suitable leaving groups include S(O)₂Me, —SMe orhalo (e.g., F, Cl, Br, I).

“Linking group” is a group that serves as an intermediate locus betweentwo or more end groups. The nature of the linking group can vary widely,and can include virtually any combination of atoms or groups useful forspacing one molecular moiety from another. For example, the linker maybe an acyclic hydrocarbon bridge (e.g, a saturated or unsaturatedalkyleno such as methano, ethano, etheno, propano, prop[1]eno, butano,but[1]eno, but[2]eno, buta[1,3]dieno, and the like), a monocyclic orpolycyclic hydrocarbon bridge (e.g., [1,2]benzeno, [2,3]naphthaleno, andthe like), a simple acyclic heteroatomic or heteroalkyldiyl bridge(e.g., —O—, —S—, —S—O—, —NH—, —PH—, —C(O)—, —C(O)NH—, —S(O)—, —S(O)₂—,—S(O)NH—, —S(O)₂NH—, —O—CH₂—, —CH₂—O—CH₂—, —O—CH═CH—CH₂—, and the like),a monocyclic or polycyclic heteroaryl bridge (e.g., [3,4]furano,pyridino, thiopheno, piperidino, piperazino, pyrazidino, pyrrolidino,and the like) or combinations of such bridges.

“Protecting group” is a group that is appended to, for example, ahydroxyl oxygen in place of a labile hydrogen atom. Suitable hydroxylprotecting group(s) include esters (acetate, ethylacetate), ethers(methyl, ethyl), ethoxylated derivatives (ethylene glycol, propyleneglycol) and the like that can be removed under either acidic or basicconditions so that the protecting group is removed and replaced with ahydrogen atom. Guidance for selecting appropriate protecting groups, aswell as synthetic strategies for their attachment and removal, may befound, for example, in Greene & Wuts, Protective Groups in OrganicSynthesis, 3d Edition, John Wiley & Sons, Inc., New York (1999) and thereferences cited therein (hereinafter “Greene & Wuts”).

The compounds of the invention that can be used as coating agentsinclude one or more moieties that render the molecule hydrophilic innature. In certain aspects, the hydrophilic portion is a hydroxyl orprotected hydroxyl group. Alternatively, the molecule can include aminefunctionality and/or an alkoxy group or polyalkyoxy group. The type andnumber of hydrophilic groups in a coating agent are sufficient toprovide the agent with a water solubility (at room temperature andoptimal pH) of at least about 0.1 mg/ml, in particular at least about0.5 mg/ml, and more particularly at least about 1 mg/ml. Given thenature of the surface coating process, coating agent solubility levelsof at least about 0.1 mg/ml are generally adequate for providing usefulcoatings of target molecules (e.g., polymer layers) on surfaces.

The compositions of the present application can thus be contrasted withother coating agents in the art, which are typically considered to beinsoluble in water (e.g., having a comparable water solubility in therange of about 0.1 mg/ml or less, and more often about 0.01 mg/ml orless). For this reason, conventional coating agents are typicallyprovided and used in solvent systems in which water is either absent oris provided as a minor (e.g., less than about 50% by volume) component.

Alternatively, the compositions of the invention can be solubilized inwater/alcohol solutions or in alcohols, such as isopropanol, butanol,methanol, ethanol, cellosolves (glycols), and the like.

Examples of moieties that help to provide hydrophilicity to thecompositions of the invention are as described above and includehydroxyl groups, polyhydric groups, alkoxy groups, polyoxyalkylenes,amines, amides and esters.

Photoreactive species are as described herein, and are sufficientlystable to be stored under conditions in which they retain suchproperties. See, e.g., U.S. Pat. No. 5,002,582, the disclosure of whichis incorporated herein by reference. Latent reactive groups can bechosen that are responsive to various portions of the electromagneticspectrum, with those responsive to ultraviolet and visible portions ofthe spectrum (referred to herein as “photoreactive”) in particular.

Photoreactive species respond to external stimuli and undergo activespecie generation with the formation of a covalent bond to an adjacentchemical structure, e.g., as provided by the same or a differentmolecule. Photoreactive species are those groups of atoms in a moleculethat retain their covalent bonds during storage but, upon activation byan external energy source, form covalent bonds with other molecules.

Photoreactive species generate active species such as free radicals andparticularly nitrenes, carbenes, and excited states of ketones uponabsorption of electromagnetic energy. Photoreactive species can bechosen to be responsive to various portions of the electromagneticspectrum, and photoreactive species that are responsive to e.g.,ultraviolet and visible portions of the spectrum, are referred to as a“photochemical group” or “photogroup.”

The use of photoreactive species in the form of photoreactive arylketones are useful, such as acetophenone, benzophenone, anthraquinone,anthrone, and anthrone-like heterocycles (i.e., heterocyclic analogs ofanthrone such as those having N, O, or S in the 10-position), or theirsubstituted (e.g., ring substituted) derivatives. Examples of arylketones include heterocyclic derivatives of anthrone, includingacridone, xanthone, and thioxanthone, and their ring substitutedderivatives. In particular, thioxanthone, and its derivatives, havingexcitation energies greater than about 360 nm are useful.

The functional groups of such ketones are preferred since they arereadily capable of undergoing an activation/inactivation/reactivationcycle. Benzophenone is a photoreactive moiety, since it is capable ofphotochemical excitation with the initial formation of an excitedsinglet state that undergoes intersystem crossing to the triplet state.The excited triplet state can insert into carbon-hydrogen bonds byabstraction of a hydrogen atom (from a support surface, for example),thus creating a radical pair. Subsequent collapse of the radical pairleads to formation of a new carbon-carbon bond. If a reactive bond(e.g., carbon-hydrogen) is not available for bonding, the ultravioletlight-induced excitation of the benzophenone group is reversible and themolecule returns to ground state energy level upon removal of the energysource. Photoactivatable aryl ketones such as benzophenone andacetophenone are of particular importance inasmuch as these groups aresubject to multiple reactivation in water and hence provide increasedcoating efficiency.

The compositions of the invention can be applied to a surface ofinterest in any suitable manner. For example, the composition can beapplied by dip coating or by dispersing the compound on the surface (forexample, by spray coating). Suitable methods of application includeapplication in solution, dipping, spray coating, knife coating, androller coating. In one aspect, the compound is applied to the surfacevia spray coating, as this application method provides increased densityof the compound on the support surface, thereby improving durability.

Linking agents can be used in any suitable manner, including by thesimultaneous or sequential attachment of a chemical compound to asurface. Linking agents of the present invention can be used to modifyany suitable surface. Where the latent reactive group of the agent is aphotoreactive group of the preferred type, it is particularly preferredthat the surface provide abstractable hydrogen atoms suitable forcovalent bonding with the activated group.

Plastics such as polyolefins, polystyrenes, poly(methyl)methacrylates,polyacrylonitriles, poly(vinylacetates), poly (vinyl alcohols),chlorine-containing polymers such as poly(vinyl) chloride,polyoxymethylenes, polycarbonates, polyamides, polyimides,polyurethanes, phenolics, amino-epoxy resins, polyesters, silicones,cellulose-based plastics, and rubber-like plastics can all be used assupports, providing surfaces that can be modified as described herein.See generally, “Plastics”, pp. 462-464, in Concise Encyclopedia ofPolymer Science and Engineering, Kroschwitz, ed., John Wiley and Sons,1990, the disclosure of which is incorporated herein by reference. Inaddition, supports such as those formed of pyrolytic carbon, parylenecoated surfaces, and silylated surfaces of glass, ceramic, or metal aresuitable for surface modification.

The method of the present invention involves the attachment of a targetmolecule to a support surface by use of the compounds of the invention.For example, a compound of the invention is provided having two or morephotoactivatable groups in the presence of a support surface. A portionof the photoactivatable groups are activated and covalently bonded tothe surface. A portion of the photoactivatable groups are allowed torevert to their inactive state and are later reactivated in order tolater bind a target molecule in order to attach the target molecule tothe surface.

The steps of the method can be performed in any suitable order. Forexample, a multifunctional compound as described herein can bephysically absorbed or adsorbed to a suitable support surface byhydrophobic interactions. Upon illumination, a portion of thephotoreactive groups (e.g., benzophenone groups) undergo covalent bondformation at the support surface by the aforementioned mechanism. Withthe absence of abstractable hydrogens in the proximity of the remainingunbonded photoreactive group(s), and removal of the illumination source,the excited state benzophenone returns to ground state energy. Theseremaining groups are then capable of being reactivated when the targetmolecule intended for immobilization is present and when the treatedsurface is exposed to another round of illumination. This method can bedescribed as a “two-step” approach, where the photoreactive reagent isapplied in the first step to create the latent reactive surface, and inthe second step, the target molecule is added for attachment to theactivated surface.

Alternatively, the method, described as a “one-step” method, providesthat the compound of the present invention is mixed in solution togetherwith the target molecule to form a composition. The resultantcomposition is used to surface modify materials in a single illuminationstep. In this case, illumination triggers not only covalent bondformation of the latent photoreactive group with the material surface,but also simultaneously triggers covalent bond formation with adjacenttarget molecules residing on the surface.

In an alternative embodiment, the composition and the target moleculecan be combined together in a one step process simultaneously withillumination.

In another alternative method, a compound of the invention is used topretreat a substrate surface prior to the application and bonding ofmolecules that have themselves been functionalized with latent reactivegroups. This method is useful in situations where a particularlydifficult substrate requires maximal coating durability. In this manner,the number of covalent bonds formed between the substrate surface andthe target molecule derivatized with latent reactive groups cantypically be increased, as compared to surface modification with adesired latent reactive group-containing target molecule alone.

Suitable target molecules for use in the present invention, forattachment to a support surface, encompass a diverse group ofsubstances. Target molecules can be used in either an underivatized formor previously derivatized. Moreover, target molecules can be immobilizedsingly or in combination with other types of target molecules.

Target molecules can be immobilized to the surface either after (e.g.,sequentially) the surface has been primed with linking agent.Alternatively, however, target molecules are immobilized during (e.g.,simultaneously with) attachment of the present linking agent to thesurface.

Typically, target molecules are selected so as to confer particulardesired properties to the surface and/or to the device or articlebearing the surface. Examples of suitable target molecules, and thesurface properties they are typically used to provide, is represented bythe following nonlimiting list:

TARGET MOLECULE FUNCTIONAL ACTIVITY Synthetic Polymers Sulfonicacid-substituted Lubricity, negatively charged surface, polyacrylamidehydrophilicity Polyacrylamide Lubricity, protein repulsion,hydrophilicity Polyethylene glycol Lubricity, cell and proteinrepulsion, hydrophilicity Polyethyleneimine Positively charged surfacePolylactic acid Bioerodible surface Polyvinyl alcohol Lubricity,hydrophilicity Polyvinyl pyrrolidone Lubricity, hydrophilicityQuaternary amine-substituted Lubricity, positively charged surfacepolyacrylamide Silicone Lubricity, hydrophobicity Conductive polymers,e.g., Electric conductivity polyvinylpyridine, polyacetylene,polypyrrole) Carbohydrates Alginic acid Lubricity, hydrophilicityCellulose Lubricity, hydrophilicity, bio- degradable glucose sourceChitosan Positively charged surface, hydrophilicity GlycogenHydrophilicity, biodegradable glucose source HeparinAntithrombogenicity, hydrophilicity, cell attachment Hyaluronic acidLubricity, negatively charged surface Pectin Lubricity, hydrophilicityMono-, di-saccharides Hydrophilicity Dextran sulfate Chromatographymedia Proteins Antibodies Antigen binding Antithrombotic agents (e.g.,Antithrombogenic surface antithrombin III) Albumin Nonthrombogenicsurface Attachment proteins/peptides Cell attachment (e.g. collagen)Enzymes Catalytic surfaces Extracellular matrix proteins/ Cellattachment and growth peptides Growth factors, proteins/peptides Cellgrowth Hirudin Antithrombogenic surface Thrombolytic proteins (e.g.,Thrombolytic activity streptokinase, plasmin, urokinase) Lipids Fattyacids Hydrophobicity, biocompatibility Mono-, di- and triglyceridesHydrophobicity, lubricity, bio- degradable fatty acid sourcePhospholipids Hydrophobicity, lubricity, bio- degradable fatty acidsource Prostaglandins/leukotrienes Nonthrombogenic surface/ immobilizedmessengers Nucleic Acids DNA Substrate for nucleases/affinity bindingRNA Substrate for nucleases/affinity binding Nucleosides, nucleotidesSource of purines, pyrimidines, enzyme cofactorsDrugs/vitamins/cofactors Enzyme cofactors Immobilized enzymes Hemecompounds Globin bindings/surface oxygenation Drugs Drug activityNonpolymeric Materials Dyes (e.g., azo dyestuffs) Coloring agentsFluorescent compounds Fluorescence (e.g., fluorescein)

In one embodiment, the compounds of the invention can be applied to acatheter to provide a lubricious coating.

Medical articles that can be fabricated from or coated or treated withthe compounds of the invention include, but are not limited to,catheters including urinary catheters and vascular catheters (e.g.,peripheral and central vascular catheters), wound drainage tubes,arterial grafts, soft tissue patches, gloves, shunts, stents, trachealcatheters, wound dressings, sutures, guide wires and prosthetic devices(e.g., heart valves and LVADs). Vascular catheters which can be preparedaccording to the present invention include, but are not limited to,single and multiple lumen central venous catheters, peripherallyinserted central venous catheters, emergency infusion catheters,percutaneous sheath introducer systems, thermodilution catheters,including the hubs and ports of such vascular catheters, leads toelectronic devices such as pacemakers, defibrillators, artificialhearts, and implanted biosensors.

The present invention provides to lubricious compositions that includeone or more hydrophilic polymer(s), such as those listed throughout thespecification, i.e., polyvinylpyrrolidone, polyacrylamide, hyaluronicacid, and/or chitosan, and one or more of the crosslinkers describedherein.

In yet another aspect, the present invention pertains to reactionproducts formed between one or more hydrophilic polymer(s), i.e.,polyvinylpyrrolidone, and the crosslinkers described herein. Thereaction product can be a coating that can advantageously be used tocoat catheters and medical devices, providing a surface that islubricious and remains moist.

The combination of one or more crosslinkers described herein and one ormore hydrophilic polymer(s), such as polyvinylpyrrolidone can becombined to form a coating mixture. This mixture can be subjected tophotoactivation. The activation can be performed on various surfaces,and in particular, on one or more surfaces of a catheter.

The hydrophilic polymer(s) that can be combined with one or more ofcrosslinkers of the invention can have a broad range of molecularweights. Advantageously, hydrophilic polymers such as PVP can beselected that include both high molecular weight components as well aslow molecular weight components. For example, BASF provides severaldifferent PVPs including K30, K90, K12, K25 and K17. The numberindicates MW in 1000s. Ranges of formulations were prepared from 50-50K90/K30 to 90-10 K90/K30, with the higher the K90 the longer the drytime of the coating. For example, PVP's can be formulated from availablemolecular weight ranges that include >75% high molecular weight PVP(90K) and <25% low molecular weight PVP (30K).

In another embodiment, the compounds of the invention can be applied toa microscope slide or “chip” for biomolecule immobilization.

Compounds encompassed by the present invention can be prepared byselection of an appropriate aryl group with a photoactivatable group andat least one group that can either act as a nucleophilic site or can beacted upon in a nucleophilic displacement reaction with a linking agent(L) having at least two opposing groups, either a leaving group(s) or anucleophilic group(s). General synthetic schemes detailed belowdemonstrate two approaches suitable to prepare compounds of theinvention.

-   -   or

wherein X is an integer equivalent to “n” and n is an integer between 2and about 6, R³ and R⁴ are as defined above, “Y” is a leaving group or agroup that can be acted upon by a nucleophilic group, such as an ester,carboxylic acid halide, etc. and “Nuc” is a nucleophilic group, asdescribed in further detail below. Alternatively, the reaction between“Y” and “Nuc” can be a condensation reaction, such as the reactionbetween, for example, a hydroxyl group and a carboxylic acid.

It should be understood in schemes I and II, that R³ and R⁴ areinterchangeable.

Suitable nucleophilic groups (Nuc) include, for example, amines,hydroxyl, thiol, etc.

Suitable leaving groups, or groups susceptible to nucleophilic attack,include esters, ethers, epoxides, halides, isocyanates, isothiocyanates,sulfonyl chlorides, anhydrides, carboxylic acid halides, carboxylic acidesters, and aldehydes.

Resultant functional moieties from the reaction between the nucleophilicgroup and leaving (or condensation group) include, for example, esters,ethers, carbamates, thiocarbamates, sulfones, amides, ureas, thiourea,amines, sulfonamides, imines (that can be further reduced with areducing agent such as sodium borohydride to an amine), etc.

Suitable reaction conditions for such condensations or nucleophilicdisplacements are known in the art. For example, hydroxyl containingmoieties can be condensed with a carboxylic acid under dehydratingconditions (refluxing toluene, acid catalyst, Dean Stark trap) to formesters. Reactive halides can be displaced by hydroxyl groups under basicconditions. An isocyanate reacts with a hydroxyl group with heat to formcarbamates. Likewise, an isothiocyanates reacts with a hydroxyl group toform a thiocarbamate. Under deprotonation conditions, a hydroxide ionreacts with an epoxide to form an ether linkage and forming a newhydroxyl group. Reaction between a hydroxyl and a sulfonyl chlorideforms a sulfone. Reaction between a hydroxyl and an anhydride will forma ester with a carboxylic acid portion as well. Reaction between ahydroxyl group and an ester will also form an ester, with the removal ofa corresponding displaced alcohol, generally under conditions that driveoff the displaced alcohol.

Much like the reactions with hydroxyl groups, amines serve in similarmanner. For example, an amine can react with an activated carboxylicacid for form an amide. Activation of a carboxylic acid can befacilitated by various methods in the art, including for example, use ofdicyclohexylcarbodiimide (DCC) that generates urea as a side product. Anisocyanate reacts with an amine to form a urea and an isothiocyanatereacts with an amine to form a thiourea.

Reaction between an amine and an epoxide will form an amine with anappended hydroxyl group from the nucleophilic displacement of theepoxide ring. Reaction between an amine and a sulfonyl chloride willform a sulfonamide. Reaction between an anhydride and an amine willafford an amide with a carboxylic portion attached to the product.Reaction between an aldehyde and an amine will form an imine which canbe further reduced to an amine. Reaction between a carboxylic acidhalide and an amine will form an amide, as well as the reaction betweena carboxylic ester and amine. Lastly, melamine type compounds can reactwith an amine to form amine linkages.

Reaction conditions to form the compounds of the invention are known inthe art. For example, suitable reaction conditions are described in“March's Advanced Organic Chemistry: Reactions, Mechanisms, andStructure, 5th Edition, John Wiley & Sons, Michael B. Smith & JerryMarch; Fieser and Fieser's Reagents for Organic Synthesis” John Wiley &Sons, NY; Vogel's Textbook of Practical Organic Chemistry (FifthEdition) by A. I. Vogel, B. S. Furniss, A. J. Hannaford, P. W. G. Smith,and A. R. Tatchell, Longman Scientific and Technical, Longman Group UK;and Advanced Organic Chemistry parts A and B” Third Edition, F. A.Carey, R. S. Sundberg, Plenum Press, NY, 1990, the contents of which areincorporated herein by reference in their entirety.

It should also be understood that each “Y” independently can bedifferent. Therefore, it is possible to have reaction products thatinclude an ether linkage as well as an ester linkage to the carbonylcontaining photoactivatable group.

An exemplary non-limiting reaction is depicted in Scheme III, in which ahydroxyl group undergoes nucleophilic addition to an ester or acidhalide or can undergo a condensation reaction between the hydroxyl groupand a carboxylic acid.

In a first embodiment, the present invention pertains to a compoundcomprising a formula:L-((D-T-C(R¹)(XP)CHR²GR³C(═O)R⁴))_(m)

wherein L is a linking group;

D is O, S, SO, SO₂, NR⁵ or CR⁶R⁷;

T is (—CH₂—)_(x), (—CH₂CH₂—O—)_(x), (—CH₂CH₂CH₂—O—)_(x),(—CH₂CH₂CH₂CH₂—O—)_(x) or forms a bond;

R¹ is a hydrogen atom, an alkyl, alkyloxyalkyl, aryl, aryloxyalkyl oraryloxyaryl group;

X is O, S, or NR⁸R⁹;

P is a hydrogen atom or a protecting group, with the provisio that P isabsent when X is NR⁸R⁹;

R² is a hydrogen atom, an alkyl, alkyloxyalkyl, aryl, aryloxyalkyl oraryloxyaryl group;

G is O, S, SO, SO₂, NR¹⁰, (CH₂)_(t)—O— or C═O;

R³ and R⁴ are each independently an alkyl, aryl, arylalkyl, heteroaryl,or an heteroarylalkyl group or, optionally, R³ and R⁴ can be tetheredtogether via (—CH₂—)_(q), (—CH₂—)_(r)C═O(—CH₂—)_(s),(—CH₂—)_(r)S(—CH₂—)_(s), (—CH₂—)_(r)S═O(—CH₂—)_(s) or(—CH₂—)_(r)S(O)₂(—CH₂—)_(s), (—CH₂—)_(r)NR(—CH₂—)_(s);

R⁵ and R¹⁰ are each independently a hydrogen atom or an alkyl, aryl orarylalkyl group;

R⁶ and R⁷ are each independently a hydrogen atom, an alkyl, aryl,arylalkyl, heteroaryl or heteroarylalkyl group;

R⁸ and R⁹ are each independently a hydrogen atom, an alkyl, aryl, orarylalkyl group;

R is a hydrogen atom, an alkyl or an aryl group;

q is an integer from 1 to about 7;

r is an integer from 0 to about 3;

s is an integer from 0 to about 3;

m is an integer from 2 to about 10;

t is an integer from 1 to about 10; and

x is an integer from 1 to about 500.

In a second embodiment of the first embodiment, L is a branched orunbranched alkyl chain having between about 2 and about 10 carbon atoms.

In a third embodiment of either of the first or second embodiments, D isO.

In a fourth embodiment of any of the first through third embodiments, Tis (—CH₂—)_(x) or (—CH₂CH₂—O—)_(x) and x is 1 or 2.

In a fifth embodiment of the any of the first through fourthembodiments, R¹ is a hydrogen atom.

In a sixth embodiment of any of the first through fifth embodiments, Xis O and P is a hydrogen atom.

In a seventh embodiment of any of the first through the sixthembodiments, R² is a hydrogen atom.

In an eighth embodiment of any of the first through the seventhembodiments, G is O.

In a ninth embodiment of any of the first through the eighthembodiments, R³ and R⁴ are each individually aryl groups.

In a tenth embodiment of any of the first through the ninth embodiments,m is 3.

In an eleventh embodiment of the first embodiment, L is

D is O, T is (—CH₂—)_(x), R¹ is a hydrogen atom, X is O, P is a hydrogenatom, R² is a hydrogen atom, G is O, R³ and R⁴ are phenyl groups, m is 3and x is 1.

In a twelfth embodiment of the first embodiment, L is (—CH₂—)_(y), D isO, T is (—CH₂—)_(x), R¹ is a hydrogen atom, X is O, P is a hydrogenatom, R² is a hydrogen atom, G is O, R³ and R⁴ are phenyl groups, m is2, x is 1 and y is an integer from 2 to about 6.

In a thirteenth embodiment of the twelfth embodiment, y is 2, 4 or 6.

In a fourteenth embodiment, the present invention pertains to a compoundcomprising a formula:L-((T-C(R¹)(XP)CHR²GR³C(═O)R⁴))_(m)

wherein L, T, R¹, X, R⁸, R⁹, P (with the provisio that P is absent whenX is NR⁸R⁹), R², G, R³, R⁴, R¹⁰, R, q, r, s, m, t, and x are as definedabove.

In a fifteenth embodiment of the fourteenth embodiment L has a formulaaccording to structure (I):

wherein A and J are each independently a hydrogen atom, an alkyl group,an aryl group, or together with B form a cyclic ring, provided when Aand J are each independently a hydrogen atom, an alkyl group, or an arylgroup then B is not present;

B is NR¹¹, O, or (—CH₂—)_(z);

provided when A, B and J form a ring, then A and J are (—CH₂—)_(z) orC═O;

R¹¹ is a hydrogen atom, an alkyl group, an aryl group or denotes a bondwith T;

each z independently is an integer from 0 to 3; and

provided when either A or J is C═O, then B is NR¹¹, O, or (—CH₂—)_(z)and z must be at least 1.

In a sixteenth embodiment of either the fourteenth or fifteenthembodiments, T is —CH₂—.

In a seventeenth embodiment of any of the fourteenth through sixteenthembodiments, R¹ is a hydrogen atom.

In an eighteenth embodiment of any of the fourteenth through seventeenthembodiments, X is O and P is a hydrogen atom.

In a nineteenth embodiment of any of the fourteenth through eighteenthembodiments, R² is a hydrogen atom.

In a twentieth embodiment of any of the fourteenth through nineteenthembodiments, G is O.

In a twenty first embodiment of any of the fourteenth through twentiethembodiments, R³ and R⁴ are each individually aryl groups.

In a twenty second embodiment of any of the fourteenth through twentyfirst embodiments, m is 3.

In a twenty third embodiment of the fifteenth embodiment, A and J areboth C═O and B is N.

In a twenty fourth embodiment of the fifteenth embodiment, A and J areboth hydrogen atoms.

In a twenty fifth embodiment, the present invention pertains to acompound comprising a formula:L-((GTZR³C(═O)R⁴))_(m)

wherein Z is C═O, COO, or CONH when T (—CH₂—)_(x);

L, T, G, R³, R⁴, R¹⁰, R, q, r, s, m, t, and x are as defined above.

In a twenty sixth embodiment of the twenty fifth embodiment, L has theformula according to structure (I):

as defined above.

In a twenty seventh embodiment of either the twenty fifth or twentysixth embodiments, T is —CH₂—.

In a twenty eighth embodiment of any of the twenty fifth through thetwenty seventh embodiments, G is O.

In a twenty ninth embodiment of any of the twenty fifth through twentyeighth embodiments, R³ and R⁴ are each individually aryl groups.

In a thirtieth embodiment of any of the twenty fifth through twentyninth embodiments, wherein m is 2.

In a thirty first embodiment of any of the twenty sixth throughthirtieth embodiments, A and J are both C═O and B is NR¹¹.

In a thirty second embodiment of the twenty sixth embodiment, A and Jare both hydrogen atoms.

In a thirty third embodiment of the twenty fifth embodiment, L has aformula according to structure (II):

wherein R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷ are each independently a hydrogenatom, an alkyl or aryl group or denotes a bond with T, provided at leasttwo of R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷ are bonded with T and each K,independently, is CH or N.

In a thirty fourth embodiment of the twenty fifth embodiment, L is C═O.

In a thirty fifth embodiment of the thirty fourth embodiment, G is NH.

In a thirty sixth embodiment of either the thirty fourth or thirty fifthembodiments, T is —CH₂CH₂O—.

In a thirty seventh embodiment of any of the thirty fourth throughthirty sixth embodiments, Z is C═O.

In a thirty eighty embodiment of any of the thirty fourth through thirtyseventh embodiments, R³ is an aryl group.

In a thirty ninth embodiment of any of the thirty fourth through thirtyeighth embodiments, R⁴ is an aryl group.

In a fortieth embodiment, the present invention pertains to a compoundcomprising a formula:L-((TGQR³C(═O)R⁴))_(m)

wherein L, T, G, R³, R³, R⁴, R¹⁰, R, q, r, s, m, t and x are as definedabove and Q is (—CH₂—)_(p), (—CH₂CH₂—O—)_(p), (—CH₂CH₂CH₂—O—)_(p) or(—CH₂CH₂CH₂CH₂—O—)_(p) and p is an integer from 1 to about 10.

In a forty first embodiment of the fortieth embodiment, L has theformula according to structure (I):

as defined above.

In a forty second embodiment if either the fortieth or forty firstembodiments, T is —CH₂—.

In a forty third embodiment of any of the fortieth through forty secondembodiments, G is O.

In a forty fourth embodiment of any of the fortieth through the fortythird embodiments, R³ and R⁴ are each individually aryl groups.

In a forty fifth embodiment of any of the fortieth through forty fourthembodiments, m is 2.

In a forty sixth embodiment of any of the forty first through fortyfifth embodiments, A and J are both C═O and B is NR¹¹.

In a forty seventh embodiment of any of the forty first through fortyfifth embodiments, A and J are both hydrogen atoms.

In a forty eighth embodiment of the fortieth embodiment, L has theformula according to structure (II):

as described above.

In a forty ninth embodiment, the present invention pertains to acompound comprising a formula:L-((—CH₂—)_(xx)C(R¹)(GR³C(═O)R⁴)₂)_(m)

wherein L, R¹, G, R³, R⁴, R¹⁰, R, q, r, s, m, t are as defined above andxx is an integer from 1 to about 10.

In a fiftieth embodiment of the forty ninth embodiment, L has theformula according to structure (I):

as defined above.

In a fifty first embodiment of the fiftieth embodiment, A and B are bothhydrogen atoms.

In a fifty second embodiment of any of the forty ninth through fiftyfirst embodiments, wherein xx is 1.

In a fifty third embodiment of any of the forty ninth through fiftysecond embodiment, wherein each R¹ is H.

In a fifty fourth embodiment of any of the forty ninth through fiftythird embodiments, wherein each G is (—CH₂—)_(t)O— and t is 1.

In a fifty fifth embodiment of any of the forty ninth through fiftyfourth embodiments, each R³ and R⁴ are each individually aryl groups.

In a fifty sixth embodiment of any of the forty ninth through fiftyfifth embodiments, wherein xx is 1, each G is (—CH₂—)_(t)O— and t is 1,each R¹ is H and each R³ and R⁴ are each individually aryl groups.

In a fifty seventh embodiment, the present invention pertains to acompound comprising the formula:L-((—C(R¹)(XP)CHR²GR³C(═O)R⁴))_(m)

wherein L, R¹, X, P, R⁸, R⁹, R², R¹⁰, G, R³, R⁴, R, q, r, s, m and t areas defined as above.

In a fifty eighty embodiment of the fifty seventh embodiment, L is

and R²⁰ and R²¹ are each individually a hydrogen atom, an alkyl group oran aryl group.

In a fifty ninth embodiment of either the fifty seventh or fifty eighthembodiments, wherein R¹ is H.

In a sixtieth embodiment of any of the fifty seventh through fifty ninthembodiments, wherein X is O.

In a sixty first embodiment of any of the fifty seventh through sixtiethembodiments, P is H.

In a sixty second embodiment of any of the fifty seventh through sixtyfirst embodiments, R² is H.

In a sixty third embodiment of any of the fifty seventh through sixtysecond embodiments, G is (—CH₂—)_(t)O— and t is 1.

In a sixty fourth embodiment of any of the fifty seventh through sixtythird embodiments, R³ and R⁴ are each individually aryl groups.

In a sixty fifth embodiment of the fifty eight embodiment, R¹ is H, X isO, P is H, R² is H, G is (—CH₂—)_(t)O—, t is 1, R³ and R⁴ are eachindividually aryl groups and R²⁰ and R²¹ are both methyl groups.

In a sixty sixth embodiment, the present invention pertains to acompound comprising the formula:L-((GR³C(═O)R⁴))_(m);

wherein L, G, R³, R⁴, R¹⁰, R, q, r, s, m and t are as defined above.

In a sixty seventh embodiment, L is

In a sixty eighty embodiment of either the sixty sixth or sixty seventhembodiments, G is C═O.

In a sixty ninth embodiment of any of sixty sixth through sixty eighthembodiments, R³ and R⁴ are each individually aryl groups.

In a seventieth embodiment of any of the sixty sixth through sixty ninthembodiments, G is C═O and R³ and R⁴ are each individually aryl groups.

In a seventy first embodiment of any of the first through seventiethembodiments, R³ and R⁴ are both phenyl groups and are tethered togethervia a CO, a S or a CH₂.

In a seventy second embodiment of any of the first through seventiethembodiments, R³ and R⁴ are both phenyl groups and include at least oneCH₃OCH₂CH₂O—.

In a seventy third embodiment, the present invention pertains to amethod to modify a substrate comprising the step of applying a compoundof any of the first through seventy second embodiments to the surface ofthe substrate, such that the substrate surface is modified.

In a seventy fourth embodiment of the seventy third embodiment, thecompound is photoactivated such that at least one photoactivatable groupwithin the compound forms a covalent bond with the surface of thesubstrate.

In a seventy fifth embodiment of the seventy fourth embodiments, whereinthe covalently bound compound is rephotoactivated in the presence of atarget molecule, such that the target molecule is bound to the surface.

In a seventy sixth embodiment of the seventy third embodiment, whereinthe compound and a target molecule are photoactivated simultaneously,such that the compound forms a covalent bond with the substrate surfaceand forms a bond with the target molecule.

In a seventy seventh embodiment, the present invention pertains to acomposition comprising a polyvinylpyrrolidone and the compound of any offirst through seventy second embodiments.

In a seventy eighty embodiment, the present invention provides areaction product formed between a polyvinylpyrrolidone and the compoundof any of the first through seventy second embodiments.

In a seventy ninth embodiments, the present invention pertains to acoating formed between a polyvinylpyrrolidone and the compound of any ofthe first through seventy second embodiments.

In an eightieth embodiment, the present invention pertains to a cathetercoated with a coating formed from a polyvinylpyrrolidone and thecompound of any of the first through seventy second embodiments.

In an eighty first embodiment, the present invention pertains to amethod to prepare a coating, comprising the steps:

combining a polyvinylpyrrolidone and a compound of any of the firstthrough seventy second embodiments, thereby forming a coating mixture;and subjecting the coating mixture to photoactivation.

In an eighty second embodiment, the present invention pertains to amethod to modify a surface of a substrate, comprising the steps:

combining a polyvinylpyrrolidone and a compound of any of the firstthrough seventy second embodiments, thereby forming a coating mixture;

coating the surface of the substrate with the coating mixture; and

subjecting the coating mixture to photoactivation.

In an eighty third embodiment, the present invention pertains to amethod to modify a surface of a catheter, comprising the steps:

combining a polyvinylpyrrolidone and a compound of any of the firstthrough seventy second embodiments, thereby forming a coating mixture;

coating the surface of the catheter with the coating mixture; and

subjecting the coating mixture to photoactivation.

In an eighty fourth embodiment, and in particular, with respect to thefourteenth embodiment, the linker can be (—OCH₂CH₂O—)_(qq),(—OCH₂CH₂CH₂O—)_(qq), (—O—(CH₂)_(ii)—O—)_(qq) or(—O(CH₂)_(ii)—O—(CH₂)_(jj)—O—)_(qq), wherein qq is an integer from 1 andabout 500, ii is an integer from 1 and about 500 and jj is an integerfrom 1 and about 500. For example, when (—OCH₂CH₂O—)_(qq) is a linker,qq can be 2, 4 or 6, thus producing linkages having diethylene,tetraethylene and hexaethylene glycol type moieties as in Examples 14,22 and 24 described below.

In an eighty fifth embodiment of the eighty fourth embodiment, L is(—OCH₂CH₂O—)_(qq), T is (—CH₂—)_(x), R¹, X, R⁸, R⁹, P (with the provisiothat P is absent when X is NR⁸R⁹), R², G, R³, R⁴, R¹⁰, R, q, r, s, m, t,qq, ii, jj and x are as defined above.

In an eighty sixth embodiment of the eighty fifth embodiment, qq is aninteger from 1 to 10, i.e., 2, 4 or 6, x is an integer from 1 to 10,i.e., 1, m is 2, R¹ is H, X is O, P is H, G is O and R³ and R⁴ are arylgroups, i.e., phenyl groups.

In an eighty seventh embodiment, the eighty fourth through the eightysixth embodiments are applicable to the seventy third through eightythird embodiments, substituting for the first through seventy secondembodiments where appropriate.

The invention will be further described with reference to the followingnon-limiting Examples. It will be apparent to those skilled in the artthat many changes can be made in the embodiments described withoutdeparting from the scope of the present invention. Thus the scope of thepresent invention should not be limited to the embodiments described inthis application, but only by embodiments described by the language ofthe claims and the equivalents of those embodiments. Unless otherwiseindicated, all percentages are by weight.

Example 1 Synthesis of Trifunctional Triazine Crosslinker

1.2 g (4 mmol) of triglycidyl isocyanurate (Aldrich Chemicals,Milwaukee, Wis.) and 2.4 g (12 mmol) of 4-hydroxybenzophenone (AldrichChemicals, Milwaukee, Wis.) were mixed in a 50-ml round bottom flaskcontaining a magnetic stir bar. The flask was flushed with argon for 10min and heated to 130° C. in an oil bath. Once the reaction mixturemelted, 6 mg (0.02 mmol) of triphenylphosphine (Aldrich Chemicals,Milwaukee, Wis.) was added. The mixture was stirred for another 2minutes under argon and cooled to room temperature. The reaction residuewas dissolved in 30 ml chloroform, then washed with 4N NaOH (30 ml×3)and deionized water (30 ml×3). The organic layer was dried overmagnesium sulfate and concentrated to dryness on the under reducedpressure. The product was purified by column chromatography (silica gel,230-400 mesh, Whatman, Inc.) using ethyl acetate as eluent (R_(f)˜4.5).The fractions containing the pure product were combined and concentratedunder reduced pressure and a white powder was obtained after dryingunder vacuum (yield 70%).

The crosslinker is soluble in most common solvents including chloroform,methylene chloride, acetone, ethyl acetate, isopropanol, etc. ¹H NMR(CDCl₃) confirmed the structure of the product. The peaks at d 7.78 ppm(m, 12H), 7.46 ppm (m, 9H), 6.98 ppm (m, 6H) were the typical signalsfrom 4-substituted benzophenone. The peak at d 4.35 ppm (m, 6H) wasassigned to the protons of methylene connected to phenoxy group. Thepeak at d 4.13 ppm (m, 9H) was a combination of 6 protons of 3 methylenegroups connected to nitrogen atom and 3 protons from 3 methine groups.The peak at d 3.00 ppm (s, 3H) corresponded to hydroxyl groups.

Example 2 Application of Triazine Crosslinker to Create a PhotoreactiveSurface

A photoreactive poly(ε-caprolactone) (PCL) film was prepared byincorporating the crosslinker in a film casting polymer solution. Asolution containing 20 mg/ml PCL (Aldrich Chemicals, Milwaukee, Wis.)and 0.4 mg/ml triazine crosslinker (as prepared in Example 1) was castonto a glass slide. 10 μl of 50 mg/ml poly(vinylpyrrolidone) (PVP), 30K,Kollidon K30 BASF, NJ) in isopropanol solution was added onto the film.After complete evaporation of the isopropanol, the film was illuminatedunder UV for 20 minutes (UV Crosslinker, UVP CL-1000, Upland, Calif.,254 nm light, 120,000 μJ/cm²). The coated film was incubated indeionized water on a shaker for 3 hours to remove unbound PVP. Ahomogeneous PVP coating could be seen on the PCL film by staining with asolution of Congo Red (0.5% w/v aqueous solution) indicating a uniformdistribution of crosslinker on the film surface. A PCL film withouttriazine crosslinker added showed no staining, indicating all unboundPVP was removed by the rinse.

Example 3 Synthesis of Photoreactive Glycol Crosslinker

2.26 g 4-hydroxybenzophenone (Aldrich Chemicals, Milwaukee, Wis.) wasdissolved in 50 ml of acetone, and 0.532 ml of glycerol triglycidylether (Polysciences, Warrington, Pa.), and 3.3 g potassium carbonate(Aldrich Chemicals, Milwaukee, Wis.) were added to the solution. Thereaction mixture was heated to reflux over 24 hours. After 24 hours ofheating, thin layer chromatography (TLC) showed consumption of theglycerol starting material (eluent 20:1 Chloroform:methanol) and theemergence of three uv active spots. The acetone was removed by rotaryevaporation and the residue was dissolved in chloroform, and filtered.The resulting chloroform solution was washed three times with 4N NaOHaqueous solution, once with deionized water, then twice with 1N HClaqueous solution, and three times again with deionized water. Thechloroform solution was dried over magnesium sulfate, filtered, and thesolvent removed by rotary evaporation. The resulting oil was washedthree times with diethyl ether and dried. This treatment removed all4-hydroxybenzophenone starting material, with TLC revealing the samethree uv active spots. These three products presumably correspond tosingle, double, and triple substitution of benzophenone on the glycerolcompound.

Example 4 Wettable Coatings with Glycol Linker

A coating solution was made up from the crude glycol linker productisolated in Example 3 (0.5 mg/ml glycol in isopropanol with 50 mg/mlpolyvinylpyrrolidone (Kollidon K30, BASF, NJ)). 100 μl of the coatingsolution was applied to PVC coverslips (Fisher Scientific, Pittsburgh,Pa.) and allowed to dry overnight. All pieces were illuminated for a settime in a uv crosslinker (UVP CL-1000, Upland, Calif., 254 nm light,120,000 μJ/cm²) from 0 to 10 minutes. Pieces were then rinsed for 30minutes in deionized water with gentle agitation. The static contactangle with water was taken on a goniometer (MicroVu 400, Santa Ana,Calif.), three 3 μl drops of water were measured, three times apiece.Contact angles are shown below.

Sample illumination time Contact Angle   0 minutes  38.1 ± 10.0 0.5minutes 28.4 ± 7.8   1 minute 31.7 ± 6.3   2 minutes 31.1 ± 4.4   5minutes 23.1 ± 8.8  10 minutes 29.1 ± 3.0 Uncoated 61.9 ± 1.4

Example 5 Higher Concentration Coating with Glycol Crosslinker

A coating solution was made up from the crude glycol linker productisolated in Example 3 (2.0 mg/ml glycol in 90:10 isopropanol:acetonewith 50 mg/ml polyvinylpyrrolidone (Kollidon K30, BASF, NJ)). 500 μl ofthe coating solution was applied to PVC coverslips (Fisher Scientific,Pittsburgh, Pa.) and allowed to dry overnight. Sample pieces wereilluminated for 0, 1, 2, or 5 minutes in a uv crosslinker (UVP CL-1000,Upland, Calif., 254 nm light, 120,000 μJ/cm²). Pieces were then rinsedfor 30 minutes in deionized water with gentle agitation. After rinsingthe pieces were stained with a solution of 3.5 mg/ml Congo Red dye indeionized water, by dipping in the solution for 30 seconds, then rinsingin deionized water. Congo Red stains the PVP giving evidence of coatedsamples. Pieces illuminated for five minutes showed bright red stains,indicating PVP, while 0, 1, and 2 minutes showed little or no red color.

Example 6 Coating with Triazine Crosslinker

A coating solution of purified triazine crosslinker isolated in Example1 was made by adding 44 mg of crosslinker to 1 ml of acetone, dilutedwith 19 ml of isopropanol, then adding 1000 mg of poly(vinylpyrrolidone)(PVP) (Kollidon K30, BASF, NJ). The resulting solution was thoroughlymixed on an orbital shaker for four hours. 18 samples were prepared byadding 100, 200, or 500 μl of coating solution onto PVC Coverslips(Fisher Scientific, Pittsburgh, Pa.) (n=6 for each condition), then airdrying. The sample pieces were illuminated for five minutes in a uvchamber (UVP CL-1000, Upland, Calif., 254 nm light, 120,000 μJ/cm²),then rinsed for four hours in deionized water with gentle agitation. 4pieces of each variable were then stained with Congo red dye todetermine the presence of PVP. For each coating condition, two of thefour stained pieces were then rubbed with a wet glove to determinedurability of the coating to simple rubbing. The results are shown inthe following table. The remaining two unstained sample pieces for eachcoating condition were then assessed for static contact angle bythreefold measurement of three 3 μl drops of water on a goniometer(MicroVu 400, Santa Ana, Calif.). Results, included in the followingtable, show that after rinsing the top monolayer of each surface ishydrophilic and presumably contains PVP.

Congo Red stain Congo red stain Contact angle Coating indicating PVPafter rubbing (rinse only) 100 ml ++ ++ 35.3 ± 3.4 200 ml ++ ++ 38.7 ±2.6 500 ml +− −− 29.2 ± 2.2

Example 7 Coating Catheters with Triazine Crosslinker

Three coating solutions were made, each with 12 mg linker (example 1), 3ml of isopropanol and 3 ml of 100 mg/ml polymer solution in isopropanolwhere the polymer solutions were composed of K30 (polyvinylpyrrolidoneMW ˜30,000, Kollidon 30 BASF), K90 (polyvinylpyrrolidone MW ˜90,000,Kollidon 90 BASF) and 1:1 K30:K90. The coating solutions were sonicated.18 1 inch sections of silicone rubber commercial catheters were cleanedwith isopropanol, then hand dipped into the coating solutions (n=6) andwithdrawn slowly. They were placed upright to dry and half were thenilluminated for 10 minutes in a uv chamber (UVP CL-1000, Upland, Calif.,254 nm light, 120,000 μJ/cm²). All sample pieces were rinsed for 30minutes in deionized water, then stained with Congo Red to detect thepresence of PVP. All illuminated sample pieces showed bright red stainindicating significant PVP, while none of the non-illuminated samplesshowed staining. There were no significant other differences between thethree coatings.

Example 8 Lubricity Formulation for Long Dry Time

A solution of 37.0 mg triazine tribenzophenone from Example 1 in 66.6 mlof 50 mg/ml polyvinylpyrrolidone (PVP, K90 from BASF Corp., FlorhamPark, N.J.) in isopropanol (Fisher Scientific, Pittsburgh, Pa.) wasdiluted with 7.4 ml of 50 mg/ml polyvinylpyrrolidone (K30, from BASFCorp., Florham Park, N.J.) in isopropanol. This solution was stirred at45° C. for 1 hour to allow thorough mixing. 9 inch pieces of PVC tubing(Hollister, Libertyville, Ill.) were coated with the solution byimmersing the pieces in the solution for 30 seconds, then extracting at0.5 cm/sec. Pieces were prepared for coating by cleaning with a briefisopropanol rub. The total coated length was 6 inches. A polyethylenemandrel was inserted in the lumen for ease of coating (0.115 inchdiameter HDPE, Small Parts, Inc. Logansport, Ind.) The pieces were airdried at room temperature for 3 minutes, then irradiated withultraviolet light (300 to 400 nm) for 3 minutes (Harland Medical UVM400,Eden Prairie, Minn.). The pieces were tested with a commercial frictiontester (Harland Medical, FTS 5000, Eden Prairie, Minn.) for lubricityand dry time.

In a lubricity test, the pieces were hydrated for 2 minutes with water,then silicone pads compressed the tubing while immersed in water as thetubing was pulled upward at 1.0 cm/sec for 6.0 cm. The clamps were thenreleased and the tubing moved freely downward 6.0 cm at 2.0 cm/sec. Thiscycle was repeated fifteen times. The average friction force required topull the coated tubing through the silicone pads with 300 g of force onthem was 5.6 g. The average friction force to pull uncoated tubingthrough the silicone pads exceeds 250 g. No significant change was seenin the friction test throughout the fifteen cycles.

In a dry test, the pieces were hydrated for 2 minutes with water,followed by 4 minutes of air drying at room temperature. The frictiontest above was repeated without any water present, simply rubbing thecoating in air. The test ran for 50 cycles rather than 15. The returnvelocity was 5.0 cm/sec instead of 2.0 cm/sec. During this time theaverage lubricity decreased from 5.6 g to 6.6 g; the coating maintainedits integrity and felt wet to the touch. The entire test lasted over 22minutes including the 4 minutes of dry time prior to rubbing. Acommercial hydrophilic catheter was compared as a control. The averagefriction force on a Mentor Self-cath Plus (Mentor, Minneapolis, Minn.)increased from 11.6 g to over 50 g in 10 cycles in less than 8 minutesof total drying time. At this point the coating felt dry to the touch.

Example 9 Lubricity on a Catheter

The coating solution from Example 8 was used to coat 6 inches of anuncoated Mentor commercial catheter (Mentor Self-cath, Minneapolis,Minn.) following the procedure in Example 1. The catheters were preparedby snipping off the end with outlets, then cleaning with an isopropanolwipe. After air drying, the catheters were dipped in the coatingsolution where they remained for 30 seconds, followed by extraction at0.5 cm/sec. The coatings dried for 3 minutes, then were irradiated for 3minutes with ultraviolet light at 300 to 400 nm (Harland Medical UVM400,Eden Prairie, Minn.). No mandrel was used for the coating.

Friction testing for lubricity followed the protocol described inExample 8. Lubricity on the coated catheter averaged 11.9 g. It showedno significant changes in the fifteen cycles.

Dry time was tested following the protocol in Example 8. The dry timefriction increased from an average of 12.6 g per cycle to 38.5 g percycle (cycle 50). The peak friction increased from 18.3 g to 280.2 g ina dramatic rise beginning in cycle 44. The coating remained wet to thetouch. As described in Example 8, the coated Mentor catheter (Self-cathPlus, Mentor, Minneapolis, Minn.) increased friction in just 10 cycles.

Example 10 Lubricity on Polyethylene Rod

A coating solution was made up of 1.0 mg/ml triazine crosslinker(Example 1), 50 mg/ml polyvinylpyrrolidone where 75% v/v is highmolecular weight (BASF K90 90,000 MW, BASF Corp. Florham Park, N.J.) and25% v/v is low molecular weight (BASF K30, 30,000 MW, BASF Corp. FlorhamPark, N.J.) in isopropanol. High density polyethylene rod (0.115 inchdiameter, Small Parts Inc, Logansport, Ind.) was cleaned withisopropanol, air dried and coated. The pieces were coated on a HarlandMedical PCX (Harland Medical, Eden Prairie, Minn.) with 9 inches coateddistance, 30 seconds dwell in solution, 0.5 cm/sec extraction speed, 2minutes dry, then were irradiated for 3 minutes with ultraviolet lightat 300 to 400 nm) (Harland Medical UVM400, Eden Prairie, Minn.).

Lubricity tests on the coated rod were performed on the Harland MedicalFTS5000. Pieces were compressed between silicone pads with 500 g forcewhile immersed in water, then pulled through the pads at 1.0 cm/sec for6.0 cm. The clamps then released and the pieces were moved downward at2.0 cm/sec. Eleven cycles were completed, with an average friction forceof 3.9 g and a peak friction force of 6.7 g.

Example 11 Lubricity on Catheter

A 6 inch segment of a Mentor Self-Cath catheter (Mentor, Minneapolis,Minn.) was coated with a solution of 0.5 mg/ml triazine crosslinker(Example 1) and 50 mg/ml PVP where 75% v/v is high molecular weight(BASF K90 90,000 MW, BASF Corp. Florham Park, N.J.) and 25% v/v is lowmolecular weight (BASF K30, 30,000 MW, BASF Corp. Florham Park, N.J.) inisopropanol. The catheters were prepared by snipping off the end withoutlets, then cleaning with an isopropanol wipe. After air drying, thecatheters were dipped in the coating solution where they remained for 30seconds, followed by extraction at 0.5 cm/sec. The coatings dried for 3minutes, then were irradiated for 3 minutes with ultraviolet light at300 to 400 nm) (Harland Medical UVM400, Eden Prairie, Minn.). No mandrelwas used for the coating.

The lubricity was tested on a Harland Medical FTS5000 (Harland Medical,Eden Prairie, Minn.) with 300 g of clamp force on silicone pads over 6cm of coated tubing as described in Example 8. The coated catheter washydrated for 2 minutes prior to the test. The average friction force was11.4 g with a peak friction force of 26.2 g.

Drying times were tested according to the protocol in Example 8.Lubricity decreased from an average frictional force of 11.4 g in cycle1 to 121.8 g in cycle 18 to over 250 g in cycle 22. Lubricity wasrelatively constant until a force increase at approximately cycle 15.

Example 12 Lubricity on a Catheter

6 inch segments of PVC tubing supplied by Hollister (Libertyville, Ill.)were coated with a solution of 0.5 mg/ml triazine crosslinker(Example 1) and 50 mg/ml PVP where 80% v/v is high molecular weight(BASF K90 90,000 MW, BASF Corp. Florham Park, N.J.) and 20% v/v is lowmolecular weight (BASF K30, 30,000 MW, BASF Corp. Florham Park, N.J.) inisopropanol. The pieces were immersed in the solution for 30 seconds,then extracting at 0.5 cm/sec. Pieces were prepared for coating bycleaning with a brief isopropanol rub. A polyethylene mandrel wasinserted in the lumen for ease of coating (0.115 inch diameter HDPE,Small Parts, Inc. Logansport, Ind.) The pieces were air dried at roomtemperature for 3 minutes, then irradiated with ultraviolet light for 3minutes at 300-400 nm (Harland Medical UVM400, Eden Prairie, Minn.). Thepieces were tested with a commercial friction tester (Harland Medical,FTS 5000, Eden Prairie, Minn.) for lubricity and dry time.

The lubricity test followed the protocol in Example 8. Averagefrictional force on the coated pieces was 5.7 g over fifteen cycles,with average peak force of 8.4 g. Coatings were slick to the touch.

Dry Time tests followed the protocol in Example 8. Average frictionalforces increased from 5.2 g (cycle 15) to 75.6 g (cycle 36) to 215.6(cycle 50). Lubricity was relatively constant between cycle 1 and cycle34. The total dry time is over 22 minutes; dry time to cycle 34 is over14 minutes.

Example 13 Lubricity on a Catheter

9 inch segments of a Mentor Self-Cath catheter (Mentor, Minneapolis,Minn.) was coated with a solution of 0.5 mg/ml triazine crosslinker(Example 1) and 50 mg/ml PVP where 70% v/v is high molecular weight(BASF K90 90,000 MW, BASF Corp. Florham Park, N.J.) and 30% v/v is lowmolecular weight (BASF K30, 30,000 MW, BASF Corp. Florham Park, N.J.) inisopropanol. The pieces were immersed in the solution for 30 seconds,then extracting at 0.5 cm/sec. Pieces were prepared for coating bycleaning with a brief isopropanol rub. A polyethylene mandrel wasinserted in the lumen for ease of coating (0.115 inch diameter HDPE,Small Parts, Inc. Logansport, Ind.) The pieces were air dried at roomtemperature for 3 minutes, then irradiated with ultraviolet light for 3minutes (Harland Medical UVM400, Eden Prairie, Minn.). The pieces weretested with a commercial friction tester (Harland Medical, FTS 5000,Eden Prairie, Minn.) for lubricity.

The lubricity test followed the protocol in Example 8. No mandrel wasused in the lubricity testing. Average frictional force on the coatedpieces was 16.2 g over nine cycles, with average peak force of 19.3 g.Coatings were slick to the touch.

Example 14 Diethylene Glycol Photocrosslinker Synthesis

4-Hydroxybenzophenone, 2.2758 g (11.4811 mMol, 2 mol eq, Alfa Aesar,Ward Hill, Mass.), was added to a 100 mL round bottom flask equippedwith a reflux condenser and dissolved in 75 mL of acetone. Ethyleneglycol diglycidyl ether, 1.0000 g (5.7405 mMol, 1 mol eq AldrichChemicals, Milwaukee, Wis.) followed by potassium carbonate, 3.1736 g(22.9621 mMol, 4 mol eq), was then added to the mixture and was heatedat reflux overnight. After cooling, the remaining solid was filtered andorganic layer was removed in vacuo. The crude product mixture wasredissolved in 60 mL of chloroform and the residual4-Hydroxybenzophenone was removed by washing with a 4N NaOH aqueoussolution. The organic layer was then dried over MgSO₄ and filtered toremove drying agent. A portion of the chloroform solvent was removed invacuo until 5 mL remained. The product was isolated by silica column(EMD Silica Gel 0.040-0.063 mm, 230-400 mesh, 60 Å) using (9:1) EthylAcetate:Hexane as eluent. Elution was monitored by TLC. R_(f) value ofdesired product was 0.40 in same eluent. ¹H NMR (CDCl₃): δ=7.7-7.9,7.4-7.6, 6.9-7.1 (m, characteristic of benzophenone), 4.2-4.3 (m),4.0-4.2 (m), 3.6-3.8 ppm (m).

Example 15 Coating with Diethylene Glycol Photocrosslinker

The coating solutions consisted of 2 mg/mL crosslinker, 1 mg/mLcrosslinker and 0.5 mg/mL crosslinker where the crosslinker was eitherthe tri-isocyanurate synthesized in Example 1, or the di-ethylene glycolsynthesized in Example 14. All coating solutions contained 50 mg/mLpolyvinylpyrrolidone (Kollidon 90, BASF#5000784, Florham Park, N.J.) inisopropanol (Fisher Scientific A416-4, Pittsburgh, Pa.). The solutionswere then incubated overnight at 60° C. to incorporate all theingredients into solution. PVC coverslips (Fisher Scientific,Pittsburgh, Pa.) were cleaned with isopropanol. 100 uL of the coatingsolutions were then deposited onto the surface of the coverslips andallowed to dry. After drying the coated samples were split into twosets: one to be illuminated and the other not. The illuminated sampleswere then placed under a UV lamp (Harland Medical UVM400, Eden Prairie,Minn.) for 5 minutes. The lamp was set to be 4 inches from the surfaceof the coverslips. After illumination all samples were then washed indeionized water for 5 minutes on a rotary shaker. The samples were thendivided once more into rubbed and unrubbed sets. The rubbed set wasrubbed between gloved fingers to determine durability. The samples werethen rinsed with deionized water and stained with the Congo Red Solution(3.5 mg/mL Congo Red (Sigma#860956, St. Louis, Mo.) in deionized water).

Results

Unilluminated Illuminated Rubbed Unrubbed Rubbed Unrubbed di-ethyleneglycol[Conc.] .5 mg/mL [−] [−] [+] [+]  1 mg/mL [−] [−] [++] [++]  2mg/mL [−] [−] [+++] [+++] Tri- isocyanurate[Conc.] .5 mg/mL [−] [−][+++] [+++]  1 mg/mL [−] [−] [+++] [+++]  2 mg/mL [−] [−] [++] [++]

Example 16 Synthesis of Urea Photo-Crosslinker

Bis-2,3-dihydroxypropylurea, 0.3000 g (1.4408 mMol, 1 mol equiv. AldrichChemicals, Milwaukee, Wis.), was added to a 50 mL round bottom flaskunder argon sweep and dissolved in 20 mL of DMF (Fisher Scientific,Pittsburgh, Pa.). Sodium hydride (60% dispersion in mineral oil, AldrichChemicals, Milwaukee, Wis.), 0.2305 g (5.7633 mMol, 4 mol eq), was thenadded and stirred at room temperature for 20 minutes.4-(Bromomethyl)benzophenone, 1.5858 g (5.7633 mMol, 4 mol equiv. AldrichChemicals, Milwaukee, Wis.), was added to the mixture and heated atreflux under positive argon pressure for five hours. After cooling, thereaction mixture was dissolved in 200 mL of deionized water and thecrude product was extracted with chloroform. The organic layer was thendried over magnesium sulfate and filtered to remove the drying agent.The chloroform was removed in vacuo and the crude product wasredissolved in a minimal amount of (85:15) CHCl₃:MeOH. The product wasisolated by silica gel column (EMD Silica Gel 0.040-0.063 mm, 230-400mesh, 60 Å) using (85:15) CHCl₃:MeOH as eluent. Elution was monitored byTLC. R_(f) value of desired product was 0.74 in the same eluent. Severalspots were isolated together and may represent two, three, and fourfunctionalized crosslinkers. ¹H NMR (CDCl₃): δ=7.3-7.9 (m,characteristic benzophenone pattern), 4.5-4.7 (m), 3.5-3.8 ppm (m).

Example 17 Coating with Urea Photo-Crosslinker

The coating solutions consisted of 2 mg/mL crosslinker, 1 mg/mLcrosslinker and 0.5 mg/mL crosslinker where the crosslinker was thephoto-urea synthesized in Example 16. All coating solutions contained 50mg/mL polyvinylpyrrolidone (Kollidon 90, BASF#5000784, Florham Park,N.J.) in isopropanol (Fisher Scientific A416-4, Pittsburgh, Pa.). Thesolutions were then incubated overnight at 60° C. to incorporate all theingredients into solution. PVC coverslips (Fisher Scientific,Pittsburgh, Pa.) were cleaned with isopropanol. 100 uL of the coatingsolutions were then deposited onto the surface of the coverslips andallowed to dry. After drying the coated samples were split into twosets: one to be illuminated and the other not. The illuminated sampleswere then placed under a UV lamp (Harland Medical UVM400, Eden Prairie,Minn.) for 5 minutes. The lamp was set to be 4 inches from the surfaceof the coverslips. After illumination all samples were then washed indeionized water for 5 minutes on a rotary shaker. The samples were thendivided once more into rubbed and unrubbed sets. The rubbed set wasrubbed between gloved fingers to determine durability. The samples werethen rinsed with deionized water and stained with the Congo Red Solution(3.5 mg/mL Congo Red (Sigma#860956, St. Louis, Mo.) in deionized water).

Results

Unilluminated Illuminated Urea[Conc.] Rubbed Unrubbed Rubbed Unrubbed .5mg/mL [−] [−] [+++] [+++]  1 mg/mL [−] [−] [++] [+++]  2 mg/mL [−] [−][++] [+++]

Example 18 Synthesis of Polyalcohol Photo-Crosslinker

3,4-O-Isopropylidene-D-mannitol, 0.5000 g (2.2498 mMol, 1 mol eq,Aldrich Chemicals, Milwaukee, Wis.), was added to a 50 mL round bottomflask equipped with a reflux condenser and dissolved in 25 mL ofchloroform under argon sweep. NaH (with 60% dispersion in mineral oil,Aldrich Chemicals, Milwaukee, Wis.), 0.2700 g (6.7495 mMol, 3 mol eq),was added and then stirred for 30 minutes. 4-(Bromomethyl)benzophenone(Aldrich Chemicals, Milwaukee, Wis.), 0.1.23808 g (4.4996 mMol, 2 moleq), was added to the mixture and heated at reflux overnight underpositive argon pressure. After cooling, the organic layer was filteredto remove precipitate. A portion of the chloroform solvent was removedin vacuo until 5 mL remained. The product was isolated by silica gelcolumn (EMD Silica Gel 0.040-0.063 mm, 230-400 mesh, 60 Å) usingchloroform as eluent. Elution was monitored by TLC. R_(f) value ofdesired product was 0.40 in the same eluent. Three compounds wereisolated and may represent different isomers of the compound. ¹H NMR(CDCl₃): δ=7.3-7.9 (m, characteristic of benzophenone pattern), 4.6-5.0(dd), 4.5-4.6 (s), 3.6-3.9 (m), 1.5-1.6 ppm (s).

Example 19 Coating with Polyalcohol Photo-Crosslinker

The coating solutions consisted of 2 mg/mL, 1 mg/mL, or 0.5 mg/mLpolyalcohol crosslinker from Example 18, with all solutions containing50 mg/mL polyvinylpyrrolidone (Kollidon 90, BASF#5000784, Florham Park,N.J.) in chloroform (Fisher Scientific, Pittsburgh, Pa.). The threesolutions were shaken until completely dissolved in solution. Highdensity polyethylene rod (Small Parts Inc, Logansport, Ind.) was thencleaned with isopropanol, then dipped into the previously made coatingsolutions and extracted at a speed of 0.5 cm/sec. After drying thecoated samples were split into two sets: one to be illuminated and theother not. The illuminated samples were then placed under a UV lamp(Harland Medical UVM400, Eden Prairie, Minn.) for 5 minutes at adistance of 4 inches from the lamp. After illumination all samples werethen washed with deionized water for 5 minutes on a rotary shaker. Thesamples were then divided once more into rubbed and unrubbed sets. Therubbed set was then rubbed between gloved fingers to determinedurability. The samples were then rinsed with deionized water andstained with the Congo Red Solution (3.5 mg/mL Congo Red (Sigma#860956,St. Louis, Mo.) in deionized water).

Unilluminated Illuminated polyalcohol[Conc.] Rubbed Unrubbed RubbedUnrubbed .5 mg/mL [−] [−] [+] [+++]  1 mg/mL [−] [−] [++] [+++]  2 mg/mL[−] [−] [+++] [+++]

Example 20 Synthesis of Photo-Uracil Crosslinker

6-Aminouracil, 0.1091 g (0.8581 mMol, 1 mol eq, Aldrich Chemicals,Milwaukee, Wis.), was added to a 100 mL round bottom flask equipped witha reflux condenser and dissolved in 50 mL of chloroform under argonsweep. 4-(Benzoyl)benzoic acid chloride, 0.4199 g (1.7161 mMol, 2 moleq, Aldrich Chemicals, Milwaukee, Wis.), 4-Dimethylaminopyridine,0.01260 g (3-5 wt % of 4-(Benzoyl)benzoic acid chloride, AldrichChemicals, Milwaukee, Wis.), and Triethylamine, 0.1042 g (1.02969 mMol,1.2 mol eq, Aldrich Chemicals, Milwaukee, Wis.) were heated at refluxunder positive argon pressure overnight. After cooling, the reactionmixture was filtered to remove precipitate. The organic layer wasremoved in vacuo and the remaining crude reaction mixture wasredissolved in a minimal amount of (9:1) CHCl₃:MeOH. The desired productwas isolated by silica gel column (EMD Silica Gel 0.040-0.063 mm,230-400 mesh, 60 Å) using the (9:1) CHCl₃:MeOH as eluent. Monitorelution by TLC. R_(f) value of desired product was 0.56 in the sameeluent.

Example 21 Coating of Photo-Uracil Crosslinker

The coating solutions consisted of 2 mg/mL, 1 mg/mL, or 0.5 mg/mLphotouracil crosslinker from Example 20, with all solutions containing50 mg/mL polyvinylpyrrolidone (Kollidon 90, BASF#5000784, Florham Park,N.J.) in chloroform (Fisher Scientific, Pittsburgh, Pa.). The threesolutions were shaken until completely dissolved in solution. Highdensity polyethylene rod (Small Parts Inc, Logansport, Ind.) was thencleaned with isopropanol, then dipped into the previously made coatingsolutions and extracted at a speed of 0.5 cm/sec. After drying thecoated samples were split into two sets: one to be illuminated and theother not. The illuminated samples were then placed under a UV lamp(Harland Medical UVM400, Eden Prairie, Minn.) for 5 minutes at adistance of 4 inches from the lamp. After illumination all samples werethen washed with deionized water for 5 minutes on a rotary shaker. Thesamples were then divided once more into rubbed and unrubbed sets. Therubbed set was then rubbed between gloved fingers to determinedurability. The samples were then rinsed with deionized water andstained with the Congo Red Solution (3.5 mg/mL Congo Red (Sigma#860956,St. Louis, Mo.) in deionized water).

Unilluminated Illuminated uracil [Conc.] Rubbed Unrubbed Rubbed Unrubbed.5 mg/mL [−] [−] [++] [+++]  1 mg/mL [−] [−] [+++] [+++]  2 mg/mL [−][−] [+++] [+++]

Example 22 Synthesis of TEG Photo-Crosslinker

1.94 g of tetraethylene glycol (Aldrich Chemicals, Milwaukee, Wis.) wasdried under vacuum at 50° C. for 2 h and dissolved in 50 ml anhydroustetrahydrofuran. 6.8 g of 4-(bromomethyl)benzophenone (AldrichChemicals, Milwaukee, Wis.) and 1.8 g sodium hydride (60% in mineraloil, Aldrich Chemicals, Milwaukee, Wis.) were added to the solution. Themixture was stirred overnight under refluxing condition and argonprotection. The reaction solution was cooled to room temperature andfiltered. The filtrate was concentrated by rotary evaporation and theresidue was purified on column chromatography (silica gel, 230-400 mesh,Whatman, Inc.) using 25:1 chloroform/methanol mixture as eluent. Thefractions containing the pure product were combined and concentrated todryness by rotary evaporation to yield yellowish oil (yield 80%).

The TEG crosslinker is soluble in most common solvents includingchloroform, methylene chloride, tetrahydrofuran, acetone, ethyl acetate,isopropanol, etc. ¹H NMR (CDCl₃) confirmed the structure of the product.The peaks at 7.49˜7.79 ppm (m, 18H) were the typical signals from4-substituted benzophenone. The peak at 4.66 ppm (s, 4H) was assigned tothe protons of methylene connected to benzophenone group. The peak at3.70 ppm (m, 16H) corresponded to ethylene groups.

Example 23 Coating with TEG Photo-Crosslinker

A coating solution was made by dissolving 0.5 g ofpoly(vinylpyrrolidone) (PVP) (Kollidon K30, BASF, NJ), 0.5 g ofpoly(vinylpyrrolidone) (PVP) (Kollidon K90, BASF, NJ) and 20 mg of TEGcrosslinker in 20 ml isopropanol. Coatings were made by adding 100 μlcoating solution onto PVC Coverslips (Fisher Scientific, Pittsburgh,Pa.) (n=5). Coatings with same PVP concentrations but withoutcrosslinker were used as controls. After air dried, the sample pieceswere illuminated for 20 min in a UV crosslinker (UVP CL-1000, Upland,Calif., 254 nm light, 120,000 μJ/cm²), then rinsed for four hours indeionized water with gentle agitation. The sample pieces were thenstained with Congo red dye to determine the presence of PVP. Thestaining results showed that the coatings with TEG crosslinker werepositive while the coatings without crosslinker were negative,indicating TEG crosslinker helped to bond PVP onto the PVC surface.

Example 24 Synthesis of HEG Photo-Crosslinker

1.70 g of hexaethylene glycol (Aldrich Chemicals, Milwaukee, Wis.) wasdried under vacuum at 50° C. for 2 h and dissolved in 50 ml anhydroustetrahydrofuran. 3.7 g of 4-(bromomethyl)benzophenone (AldrichChemicals, Milwaukee, Wis.) and 1.5 g sodium hydride (60% in mineraloil, Aldrich Chemicals, Milwaukee, Wis.) were added to the solution. Themixture was stirred overnight under refluxing condition and argonprotection. The reaction solution was cooled to room temperature andfiltered. The filtrate was concentrated by rotary evaporation and theresidue was purified on column chromatography (silica gel, 230-400 mesh,Whatman, Inc.) using 25:1 chloroform/methanol mixture as eluent. Thefractions containing the pure product were combined and concentrated todryness by rotary evaporation to yield yellowish oil (yield 70%).

The HEG crosslinker is very soluble in most common solvents includingchloroform, methylene chloride, tetrahydrofuran, acetone, ethyl acetate,isopropanol, etc and slightly soluble in water. ¹H NMR (CDCl₃) confirmedthe structure of the product. The peaks at 7.26˜7.79 ppm (m, 18H) werethe typical signals from 4-substituted benzophenone. The peak at 4.64ppm (s, 4H) was assigned to the protons of methylene connected tobenzophenone group. The peak at 3.66 ppm (m, 24H) corresponded toethylene groups.

Example 25 Coating with HEG Photo-Crosslinker

A coating solution was made by dissolving 0.5 g ofpoly(vinylpyrrolidone) (PVP) (Kollidon K30, BASF, NJ), 0.5 g ofpoly(vinylpyrrolidone) (PVP) (Kollidon K90, BASF, NJ) and 20 mg of HEGcrosslinker in 20 ml isopropanol. Coatings were made by adding 100 μlcoating solution onto PVC Coverslips (Fisher Scientific, Pittsburgh,Pa.) (n=5). Coatings with same PVP concentrations but withoutcrosslinker were used as controls. After air dried, the sample pieceswere illuminated for 20 min in a UV crosslinker (UVP CL-1000, Upland,Calif., 254 nm light, 120,000 μJ/cm²), then rinsed for four hours indeionized water with gentle agitation. The sample pieces were thenstained with Congo red dye to determine the presence of PVP. Thestaining results showed that the coatings with HEG crosslinker werepositive while the coatings without crosslinker were negative,indicating HEG crosslinker helped to bond PVP onto the PVC surface.

Explanation of + scale for examples 14 through 25. +++ indicates a fullcoating, no obvious removal of coating from the piece and a bright redcolor. ++ is slight removal but majority is still intact, color is stillred but may be slightly less red or blotchy. + indicates significantremoval of coating, but still coating present. The color is typicallypink. In most cases the color is simply less as part of the coating isrubbed away fairly uniformly. − indicates no coating remains, no colorat all from the stain.

Although the present invention has been described with reference topreferred embodiments, persons skilled in the art will recognize thatchanges may be made in form and detail without departing from the spiritand scope of the invention. All references cited throughout thespecification, including those in the background, are incorporatedherein in their entirety. Those skilled in the art will recognize, or beable to ascertain, using no more than routine experimentation, manyequivalents to specific embodiments of the invention describedspecifically herein. Such equivalents are intended to be encompassed inthe scope of the following claim.

What is claimed is:
 1. A compound of formula:L-(D-CH₂CH(OP)CH₂GR³C(═O)R⁴)_(m) wherein L is a branched or unbranchedalkyl chain having between about 2 and about 10 carbon atoms; D is O; Pis a hydrogen atom or a protecting group; G is O; R³ and R⁴ are, eachindependently, aryl; and m is an integer from 2 to about
 10. 2. A methodto modify a substrate comprising the step of applying a compoundcomprising the formula of claim 1 to a surface of a substrate, such thatthe substrate surface is modified.
 3. The method of claim 2, wherein thecompound is photoactivated such that at least one photoactivatable groupwithin the compound forms a bond with the surface of the substrate.
 4. Acompound of formula:L-(T-C(R¹)(XP)CHR²GR³C(═O)R⁴)_(m) wherein L is a branched or unbranchedalkyl chain having between about 2 and about 10 carbon atoms; T is(—CH₂—)_(x), or forms a bond; R¹ is a hydrogen atom, an alkyl,alkyloxyalkyl, aryl, aryloxyalkyl or aryloxyaryl group; X is O, P is ahydrogen atom or a protecting group; R² is a hydrogen atom, an alkyl,alkyloxyalkyl, aryl, aryloxyalkyl or aryloxyaryl group; G is O; R³ andR⁴ are, each independently, aryl; x is an integer from 1 to about 500;and m is an integer from 2 to about
 10. 5. A method to modify asubstrate comprising the step of applying a compound comprising theformula of claim 4 to a surface of a substrate, such that the substratesurface is modified.
 6. The method of claim 4, wherein the compound isphotoactivated such that at least one photoactivatable group within thecompound forms a bond with the surface of the substrate.
 7. A compoundof formula:L-(TGQR³C(═O)R⁴)_(m) wherein L is a branched or unbranched alkyl chainhaving between about 2 and about 10 carbon atoms; T is (—CH₂—)_(x), orforms a bond; G is O; Q is (—CH₂—)_(p), (—CH₂CH₂—O—)_(p),(—CH₂CH₂CH₂—O—)_(p) or (—CH₂CH₂CH₂CH₂—O—)_(p); R³ and R⁴ are, eachindependently, aryl; p is an integer from 1 to about 10; x is an integerfrom 1 to about 500; and m is an integer from 2 to about
 10. 8. A methodto modify a substrate comprising the step of applying a compoundcomprising the formula of claim 7 to a surface of a substrate, such thatthe substrate surface is modified.
 9. The method of claim 8, wherein thecompound is photoactivated such that at least one photoactivatable groupwithin the compound forms a bond with the surface of the substrate.